Substituted quinoxaline compounds as inhibitors of fgfr tyrosine kinases

ABSTRACT

Provided herein are 7-((3,5-dimethoxyphenyl)amino)quinoxaline derivatives of the general Formula I; and stereoisomers and pharmaceutically acceptable salts or solvates thereof, in which X 2  is N and Ring A, Ring B, Ring C, X 1 , X 3 , R 1 , L, and W have the meanings given in the specification, which are inhibitors of FGFR1, FGFR2, FGFR3 and/or FGFR4 and are useful in the treatment and prevention of diseases which can be treated with an FGFR inhibitor, such as e.g. cancer, e g. bladder cancer, brain cancer, breast cancer, cholangiocarcinoma, head and neck cancer, lung cancer, multiple myeloma, rhabdomyosarcoma, urethral cancer and uterine cancer. The present description discloses the preparation of exemplary compounds as well as pharmacological data thereof (e.g. pages 276 to 308; examples 1 to 30; examples A to E; tables CA to EE). An exemplary compound is e.g. 1-(3-(4-(4-(7-((3,5-dimethoxy phenyl) amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carbonyl) azetidin-1-yl)prop-2-en-1-one (e.g. example 1).

BACKGROUND

The present disclosure relates to novel compounds that exhibitinhibition of fibroblast growth factor receptor tyrosine kinases(FGFRs), in particular FGFR1, FGFR2, FGFR3 and/or FGFR4, pharmaceuticalcompositions comprising the compounds, to processes for making thecompounds, and the use of the compounds in therapy. More particularly,it relates to substituted quinoxaline compounds useful in the treatmentor prevention of diseases which can be treated with an FGFR inhibitor,including diseases mediated by FGFR tyrosine kinases.

Fibroblast growth factors (FGFs) and their receptors (FGFRs) regulate awide range of physiologic cellular processes, such as embryonicdevelopment, differentiation, proliferation, survival, migration, andangiogenesis.

The FGF family comprises 18 secreted ligands (FGFs) which are readilysequestered to the extracellular matrix by heparin sulfate proteoglycans(HPSGs). For signal propagation, FGFs are released from theextracellular matrix by proteases or specific FGF-binding proteins, withthe liberated FGFs subsequently binding to a cell surface FGF-receptor(FGFR) in a ternary complex consisting of FGF, FGFR and HPSG (Beenken,A., Nat. Rev. Drug Discov. 2009; 8:235-253).

There are five FGFRs, of which four (FGFRs 1-4) are highly conservedsingle-pass transmembrane tyrosine kinase receptors (Eswarakumar, V. P.,Cytokine Growth Factor Rev., 2005; 16:139-149). The binding of an FGF toan FGFR leads to receptor dimerization and transphosphorylation oftyrosine kinase domains (Died, M. V., et al., Cancer Discov. 2013;3:264-279; Korc, N., and Friesel, R. E., Curr. Cancer Drug Targets 2009;5:639-651). Activation of downstream signaling occurs via theintracellular receptor substrate FGFR substrate 2 (FRS2) andphospholipase Cγ (PLC-γ), leading to subsequent upregulation ofRAS/mitogen-activated protein kinase (MAPK) and phosphoinositide3-kinase (PI3K)/AKT signaling pathways. Other pathways can be activated,including STAT-dependent signaling (Turner, N., Grose, R., Nat. Ref.Cancer 2010; 10:116-129; Brooks, N. S., et al., Clin Cancer Res. 2012;18:1855-1862; Dienstmann, R., et al., Ann. Oncol. 2014; 25:552-563).

FGFR signaling components are frequently altered in human cancer, andseveral preclinical models have provided compelling evidence for theoncogenic potential of aberrant FGFR signaling in carcinogenesis,thereby validating FGFR signaling as an attractive target for cancertreatment.

The mechanisms by which FGFR signaling is dysregulated and drive cancerare better understood in recent years, and include activating mutations,FGFR gene amplification, chromosomal translocations, autocrine andparacrine signaling, and altered FGFR splicing.

SUMMARY OF THE INVENTION

It has now been found that substituted quinoxaline compounds areinhibitors of FGFR1, FGFR2, FGFR3 and/or FGFR4, which are useful in thetreatment or prevention of diseases which can be treated with aninhibitor of FGFR1, FGFR2, FGFR3 and/or FGFR4, including diseasesmediated by FGFR1, FGFR2, FGFR3 and/or FGFR4.

Accordingly, provided herein is a compound of the general Formula I:

or pharmaceutically acceptable salt or solvate thereof, wherein Ring A,Ring B, Ring C, X¹, X², X³, R¹, L, and W are as defined herein.

Also provided herein is a pharmaceutical composition comprising acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof, in admixture with a pharmaceutically acceptable diluent orcarrier.

Also provided herein is a compound of Formula I, wherein the compound isat least about 3-fold more selective for FGFR3 than FGFR1.

Also provided herein is a compound of Formula I, wherein the compound isat least about 3-fold more selective for FGFR2 than FGFR1.

Also provided herein is a compound of Formula I, wherein the compoundforms a covalent bond with a cysteine in a kinase insert domain in aFGFR3 protein.

Also provided herein is a compound of Formula I, wherein the compoundforms a covalent bond with a cysteine in a c-terminal tail in a FGFR2protein.

Also provided herein is a pharmaceutical composition, comprising acompound according to Formula I in admixture with a pharmaceuticallyacceptable diluent or carrier.

Also provided herein is a compound of Formula I covalently bonded to acysteine.

Also provided herein is a FGFR3 inhibitor of Formula I that is at leastabout 3-fold more selective for FGFR3 than for FGFR1.

Also provided herein is a FGFR2 inhibitor of Formula I that is at leastabout 3-fold more selective for FGFR2 than for FGFR1.

Also provided herein is an inhibited FGFR3 protein covalently bound to amolecule via a cysteine in the kinase insert domain of the FGFR3protein.

Also provided herein is an inhibited FGFR2 protein covalently bound to amolecule via a cysteine in the c-terminal tail of the FGFR2 protein.

Also provided herein is an inhibited FGFR protein covalently bonded viaa cysteine to a compound of Formula I.

Also provided herein is a method for treating cancer in a subject inneed thereof, the method comprising administering a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundaccording to Formula I or a pharmaceutically acceptable salt or solvatethereof.

Also provided herein is a method for treating cancer in a subject inneed thereof, the method comprising determining if the cancer exhibits adysregulation of a FGFR gene, a FGFR kinase, or expression or activityor level of any of the same, and if the cancer is determined to exhibita dysregulation of a FGFR gene, a FGFR kinase, or expression or activityor level of any of the same, administering to the subject atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof.

Also provided herein is a method of treating a FGFR-associated cancer ina subject, the method comprising administering to a subject identifiedor diagnosed as having a FGFR-associated cancer a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof, to the subject.

Also provided herein is a method of treating cancer in a subject, themethod comprising administering a therapeutically effective amount of acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof, to a subject having a clinical record that indicates that thesubject has a dysregulation of a FGFR gene, a FGFR kinase, or expressionor activity or level of any of the same.

Also provided herein is a method of treating a FGFR-associated cancer ina subject, the method comprising determining that the cancer in thesubject is a FGFR-associated cancer, and administering to a subjectdetermined to have a FGFR-associated cancer a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof.

Also provided herein is a method of treating a subject having a cancer,wherein the method comprises administering one or more doses of a firstFGFR inhibitor to the subject for a period of time, after administeringthe one or more doses of a first FGFR inhibitor to the subject for aperiod of time, determining whether a cancer cell in a sample obtainedfrom the subject has at least one FGFR inhibitor resistance mutationthat confers increased resistance to a cancer cell or tumor to treatmentwith the first FGFR inhibitor, and administering a compound of Formula Ior a pharmaceutically acceptable salt or solvate thereof as amonotherapy or in conjunction with an additional therapy or therapeuticagent to the subject if the subject has a cancer cell that has at leastone FGFR inhibitor resistance mutation that confers increased resistanceto a cancer cell or tumor to treatment with the first FGFR inhibitor, oradministering additional doses of the first FGFR inhibitor to thesubject if the subject has a cancer cell that does not have a FGFRinhibitor resistance mutation that confers increased resistance to acancer cell or tumor to treatment with the first FGFR inhibitor.

Also provided herein is a method of treating a subject having a cancer,wherein the method comprises determining whether a cancer cell in asample obtained from a subject having a cancer and previouslyadministered one or more doses of a first FGFR inhibitor has one or moreFGFR inhibitor resistance mutations that confer increased resistance toa cancer cell or tumor to treatment with the first FGFR inhibitor thatwas previously administered to the subject, and administering a compoundof Formula I or a pharmaceutically acceptable salt or solvate thereof asa monotherapy or in conjunction with an additional therapy ortherapeutic agent to the subject if the subject has a cancer cell thathas at least one FGFR inhibitor resistance mutation that confersincreased resistance to a cancer cell or tumor to treatment with thefirst FGFR inhibitor that was previously administered to the subject, oradministering additional doses of the first FGFR inhibitor to thesubject if the subject has cancer cell that does not have a FGFRinhibitor resistance mutation that confers increased resistance to acancer cell or tumor to treatment with the first FGFR inhibitorpreviously administered to the subject.

Also provided herein is a method of treating a subject having a cancer,wherein the method comprises administering one or more doses of acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof for a period of time, after administering one or more doses of acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof for a period of time, determining whether a cancer cell in asample obtained from the subject has one or more FGFR inhibitorresistance mutations that confer increased resistance to a cancer cellor tumor to treatment with the compound of Formula I or apharmaceutically acceptable salt or solvate thereof, and administering asecond FGFR inhibitor or a second compound of Formula I or apharmaceutically acceptable salt or solvate thereof as a monotherapy orin conjunction with an additional therapy or therapeutic agent to asubject having a cancer cell that has one or more FGFR inhibitorresistance mutations that confer increased resistance to a cancer cellor tumor to treatment with the compound of Formula I or apharmaceutically acceptable salt or solvate thereof, or administeringadditional doses of the compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof to a subject having a cancer cellthat does not have a FGFR inhibitor resistance mutation that confersincreased resistance to a cancer cell or tumor to treatment with thecompound of Formula I or a pharmaceutically acceptable salt or solvatethereof

Also provided herein is a method of treating a subject having a cancer,wherein the method comprises determining whether a cancer cell in asample obtained from a subject having a cancer and previouslyadministered one or more doses of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof has one or more FGFRinhibitor resistance mutations that confer increased resistance to acancer cell or tumor to treatment with the compound of Formula I or apharmaceutically acceptable salt or solvate thereof that was previouslyadministered to the subject, administering a second FGFR inhibitor or asecond compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof as a monotherapy or in conjunction with an additionaltherapy or therapeutic agent to a subject having a cancer cell that hasone or more FGFR inhibitor resistance mutations that confer increasedresistance to a cancer cell or tumor to treatment the compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof thatwas previously administered to the subject, or administering additionaldoses of the compound of Formula I or a pharmaceutically acceptable saltor solvate thereof previously administered to a subject having a cancercell that does not have a FGFR inhibitor resistance mutation thatconfers increased resistance to a cancer cell or tumor to treatment withthe compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof that was previously administered to the subject.

Also provided herein is a method of treating a FGFR-associated cancer ina subject, the method comprising administering one or more doses of acompound of Formula I, or a pharmaceutically acceptable salt or solvatethereof, as a monotherapy to a subject identified or diagnosed as havinga FGFR-associated cancer, after administering one or more doses of acompound of Formula I, or a pharmaceutically acceptable salt or solvatethereof, as a monotherapy to the subject identified or diagnosed ashaving a FGFR-associated cancer, determining a level of circulatingtumor DNA in a biological sample obtained from the subject,administering a therapeutically effective amount of a compound ofFormula I, or a pharmaceutically acceptable salt or solvate thereof, andan additional therapy or therapeutic agent to a subject identified ashaving about the same or an elevated level of circulating tumor DNA ascompared to a reference level of circulating tumor DNA.

Also provided herein is a method of treating a FGFR-associated cancer ina subject, the method comprising administering a therapeuticallyeffective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt or solvate thereof, and an additional therapy ortherapeutic agent to a subject (i) identified or diagnosed as having aFGFR-associated cancer, (ii) previously administered one or more dosesof the compound of Formula I, or a pharmaceutically acceptable salt orsolvate thereof, as a monotherapy, and (iii) after administration of theone or more doses of the compound of Formula I, or a pharmaceuticallyacceptable salt or solvate thereof, as a monotherapy, identified ashaving about the same or an elevated level of circulating tumor DNA ascompared to a reference level of circulating tumor DNA.

Also provided herein is a method of treating a FGFR-associated cancer ina subject, the method comprising identifying a subject having aFGFR-associated cancer and an elevated serum phosphate level followingadministration of one or more doses of a first FGFR1 inhibitor, andadministering to the identified subject a compound of Formula I or apharmaceutically acceptable salt or solvate thereof.

Also provided herein is a method of treating a subject identified ashaving an elevated serum phosphate level and a FGFR-associated cancer,the method comprising administering to the subject a compound of FormulaI or a pharmaceutically acceptable salt or solvate thereof.

Also provided herein is a method for treating a FGFR-associated cancerin a subject in need of such treatment, the method comprising detectinga dysregulation of a FGFR gene, a FGFR kinase, or the expression oractivity or level of any of the same in a sample from the subject,administering to the subject a therapeutically effective amount of afirst FGFR1 inhibitor, determining whether a sample from a subjectexhibits an elevated serum phosphate level, and administering a compoundof Formula I, or a pharmaceutically acceptable salt of solvate thereofas a monotherapy or in conjunction with an additional therapy ortherapeutic agent to the subject if the sample from the subject exhibitsan elevated serum phosphate level, or administering additional doses ofthe first FGFR1 inhibitor to the subject if the sample from the subjectdoes not exhibit an elevated serum phosphate level.

Also provided herein is a method for treating a FGFR-associated cancerin a subject in need of such treatment, the method comprisingdetermining whether a sample from a subject previously administered oneor more doses of a first FGFR1 inhibitor exhibits an elevated serumphosphate level, and administering a compound of Formula I, or apharmaceutically acceptable salt of solvate thereof as a monotherapy orin conjunction with an additional therapy or therapeutic agent to thesubject if the sample from the subject exhibits an elevated serumphosphate level, or administering additional doses of the first FGFR1inhibitor to the subject if the sample from the subject does not exhibitan elevated serum phosphate level.

Also provided herein is a method for treating a FGFR-associated cancerin a subject in need of such treatment, the method comprisingidentifying a subject having a FGFR-associated cancer and previouslydemonstrating an elevated serum phosphate level, and administering tothe subject a compound of Formula I or a pharmaceutically acceptablesalt or solvate thereof.

Also provided herein is a method for treating a FGFR-associated cancerin a subject in need of such treatment, the method comprisingidentifying a subject having a FGFR-associated cancer and previouslyadministered one or more doses of a first FGFR1 inhibitor and previouslydemonstrating an elevated serum phosphate level, and administering tothe subject a compound of Formula I or a pharmaceutically acceptablesalt or solvate thereof.

Also provided herein is a method of treating a subject having a cancer,wherein the method comprises administering one or more doses of acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof for a period of time, after administering one or more doses of acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof for a period of time, determining whether a cancer cell in asample obtained from the subject has a FGFR resistance mutation in acysteine that confers increased resistance to a cancer cell or tumor totreatment with the compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof, and administering a second FGFRinhibitor as a monotherapy or in conjunction with an additional therapyor therapeutic agent to a subject having a cancer cell that has a FGFRresistance mutation in a cysteine that confers increased resistance to acancer cell or tumor to treatment with the compound of Formula I or apharmaceutically acceptable salt or solvate thereof, or administeringadditional doses of the compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof to a subject having a cancer cellthat does not have a FGFR resistance mutation in a cysteine that confersincreased resistance to a cancer cell or tumor to treatment with thecompound of Formula I or a pharmaceutically acceptable salt or solvatethereof.

Also provided herein is a method for treating a FGFR-associated cancerin a subject in need of such treatment, the method comprising detectinga dysregulation of a FGFR gene, a FGFR kinase, or the expression oractivity or level of any of the same in a sample from the subject,administering to the subject a therapeutically effective amount of aFGFR inhibitor, determining whether a sample from a subject exhibits adysregulation of a second kinase gene, a second kinase, or theexpression or activity or level of any of the same in a sample from thesubject, and administering an inhibitor of the second kinase inconjunction with an additional therapy or therapeutic agent to thesubject if the sample from the subject exhibits a dysregulation of asecond kinase gene, a second kinase, or the expression or activity orlevel of any of the same, or administering additional doses of the FGFRinhibitor to the subject if the sample from the subject does not exhibita dysregulation of a second kinase gene, a second kinase, or theexpression or activity or level of any of the same.

Also provided herein is a method for treating a FGFR-associated cancerin a subject in need of such treatment, the method comprising detectinga dysregulation of a FGFR gene, a FGFR kinase, or the expression oractivity or level of any of the same in a sample from the subject,administering to the subject a therapeutically effective amount of acompound of Formula I in conjunction with an inhibitor of a secondkinase.

Also provided herein is a method for treating a FGFR-associated cancerin a subject in need of such treatment, the method comprisingdetermining whether a sample from a subject previously administered oneor more doses of a compound of Formula I exhibits a dysregulation of asecond kinase gene, a second kinase, or the expression or activity orlevel of any of the same, and administering an inhibitor of the secondkinase in conjunction with an additional therapy or therapeutic agent tothe subject if the sample from the subject exhibits a dysregulation of asecond kinase gene, a second kinase, or the expression or activity orlevel of any of the same, or administering additional doses of thecompound of Formula I to the subject if the sample from the subject doesnot exhibit a dysregulation of a second kinase gene, a second kinase, orthe expression or activity or level of any of the same.

Also provided herein is a method for treating a cancer in a subject inneed of such treatment, the method comprising detecting a dysregulationof a first kinase gene, a first kinase, or the expression or activity orlevel of any of the same in a sample from the subject, administering tothe subject a therapeutically effective amount of an inhibitor of thefirst kinase, determining whether a sample from a subject exhibits adysregulation of a FGFR gene, a FGFR kinase, or the expression oractivity or level of any of the same, and administering a FGFR inhibitorin conjunction with an additional therapy or therapeutic agent to thesubject if the sample from the subject exhibits a dysregulation of aFGFR gene, a FGFR kinase, or the expression or activity or level of anyof the same, or administering additional doses of the inhibitor of thefirst kinase to the subject if the sample from the subject does notexhibit a dysregulation of a FGFR gene, a FGFR kinase, or the expressionor activity or level of any of the same.

Also provided herein is a method for treating a cancer in a subject inneed of such treatment, the method comprising detecting a dysregulationof a first kinase gene, a first kinase, or the expression or activity orlevel of any of the same in a sample from the subject, and administeringto the subject a therapeutically effective amount of an inhibitor of thefirst kinase in conjunction with a FGFR inhibitor to the subject if thesample from the subject exhibits a dysregulation of a FGFR gene, a FGFRkinase, or the expression or activity or level of any of the same.

Also provided herein is a method for treating a cancer in a subject inneed of such treatment, the method comprising determining whether asample from a subject exhibits a dysregulation of a FGFR gene, a FGFRkinase, or the expression or activity or level of any of the same in asubject previously administered an inhibitor of a first kinase, andadministering a FGFR inhibitor in conjunction with an additional therapyor therapeutic agent to the subject if the sample from the subjectexhibits a dysregulation of a FGFR gene, a FGFR kinase, or theexpression or activity or level of any of the same, or administeringadditional doses of the inhibitor of the first kinase to the subject ifthe sample from the subject does not exhibit a dysregulation of a FGFRgene, a FGFR kinase, or the expression or activity or level of any ofthe same.

Also provided herein is a method of treating a subject having a cancer,wherein the method comprises administering one or more doses of a firsttherapeutic agent to the subject for a period of time, afteradministering one or more doses of the first therapeutic agent to thesubject for a period of time, determining whether a cancer cell in asample obtained from the subject has at least one FGFR inhibitorresistance mutation that confers increased resistance to a cancer cellor tumor to treatment with the first therapeutic agent, andadministering a second FGFR inhibitor as a monotherapy or in conjunctionwith an additional therapy or therapeutic agent to the subject if thesubject has a cancer cell that has at least one FGFR inhibitorresistance mutation that confers increased resistance to a cancer cellor tumor to treatment with the first therapeutic agent, or administeringadditional doses of the FGFR inhibitor to the subject if the subject hasa cancer cell that does not have a FGFR inhibitor resistance mutationthat confers increased resistance to a cancer cell or tumor to treatmentwith the first therapeutic agent, and wherein the mutation correspondsto (i) amino acid position 561 of SEQ ID NO: 1, (ii) amino acid position564 of SEQ ID NO: 3, (iii) amino acid position 555 of SEQ ID NO: 5, or(iv) amino acid position 550 of SEQ ID NO: 7.

Also provided herein is a method of treating a subject having a cancer,wherein the method comprises determining whether a cancer cell in asample obtained from a subject having a cancer and previouslyadministered one or more doses of a first therapeutic agent has one ormore FGFR inhibitor resistance mutations that confer increasedresistance to a cancer cell or tumor to treatment with the firsttherapeutic agent previously administered to the subject, andadministering a second FGFR inhibitor to the subject as a monotherapy orin conjunction with an additional therapy or therapeutic agent to thesubject if the subject has a cancer cell that has at least one FGFRinhibitor resistance mutation that confers increased resistance to acancer cell or tumor to treatment with the first therapeutic agent thatwas previously administered to the subject, or administering additionaldoses of the first therapeutic agent that was previously administered tothe subject if the subject has cancer cell that does not have a FGFRinhibitor resistance mutation that confers increased resistance to acancer cell or tumor to treatment with the first therapeutic agent thatwas previously administered to the subject.

Also provided herein is a method of treating a subject, the methodcomprising administering a therapeutically effective amount of acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof, to a subject having a clinical record that indicates that thesubject has a dysregulation of a FGFR gene, a FGFR kinase, or expressionor activity or level of any of the same.

Also provided herein is a method of treating a subject, the methodcomprising administering a therapeutically effective amount of acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof, to a subject having a dysregulation of a FGFR gene, a FGFRkinase, or expression or activity or level of any of the same.

Also provided herein a method of treating a subject with aFGFR-associated disease or disorder, the method comprising administeringa therapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof to a subject with aFGFR-associated disease or disorder.

Also provided herein is a method of treating a subject, the methodcomprising detecting a dysregulation of a FGFR gene, a FGFR kinase, orexpression or activity or level of any of the same, and administering tothe subject a therapeutically effective amount of a compound of FormulaI or a pharmaceutically acceptable salt or solvate thereof.

Also provided herein is a method of treating achondroplasia,hypochondroplasia, or thanatophoric dysplasia in a subject, the methodcomprising administering to a subject identified or diagnosed as havingachondroplasia, hypochondroplasia, or thanatophoric dysplasia atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof, to the subject.

Also provided herein is a method for inhibiting angiogenesis in asubject in need thereof, the method comprising administering to thesubject a therapeutically effective amount of a compound of Formula I,or a pharmaceutically acceptable salt or solvate thereof.

Also provided herein is a method of treating a FGFR-associated cancer ina subject in need thereof, the method comprising administering to thesubject a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof wherein following administration of the compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof, asample from the subject has a phosphate level that is lower than thephosphate level of a sample from a second subject having aFGFR-associated cancer following administration of a compound that isnot a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof.

Also provided herein is a method of treating a FGFR-associated cancer ina subject in need thereof, the method comprising administering to thesubject a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof, wherein following administration of the compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof, asample from the subject does not demonstrate an elevated serum phosphatelevel.

Also provided herein is a method of reducing the risk ofhyperphosphatemia in a subject with an FGFR-associated cancer, themethod comprising administering to the subject a compound of Formula Ior a pharmaceutically acceptable salt or solvate thereof.

Also provided herein is a method of changing the adverse effects oftreatment of a subject with a FGFR-associated cancer, the methodcomprising administering to the subject a compound of Formula I or apharmaceutically acceptable salt or solvate thereof, and reducing a doseof a FGFR1 inhibitor administered to the subject, not administering aFGFR1 inhibitor to the subject, or ceasing to administer a FGFR1inhibitor to the subject.

Also provided herein is a method of reversing an elevated serumphosphate level in a subject with a FGFR-associated cancer being treatedwith a FGFR1 inhibitor, the method comprising reducing the dose orceasing administration of the FGFR1 inhibitor, and administering to thesubject a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof.

Also provided herein is use of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof for the manufactureof a medicament for treating a FGFR-associated cancer in a subject.

Also provided herein is a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof for use in treating a subjectidentified or diagnosed as having a FGFR-associated cancer.

Also provided herein is a method for inhibiting FGFR kinase activity ina mammalian cell, the method comprising contacting the mammalian cellwith a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof.

Also provided herein is a method of selecting a treatment for a subject,the method comprising selecting a treatment comprising administration ofa therapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof, for a subjectidentified or diagnosed as having a FGFR-associated cancer.

Also provided herein is a method of selecting a treatment for a subjecthaving a cancer, the method comprising determining that the cancer inthe subject is a FGFR-associated cancer, and selecting a treatmentincluding administration of a therapeutically effective amount of acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof, for a subject determined to have a FGFR-associated cancer.

Also provided herein is a method of selecting a subject for treatmentincluding administration of a therapeutically effective amount of acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof, the method comprising identifying a subject having aFGFR-associated cancer, and selecting the subject for treatmentincluding administration of a therapeutically effective amount of acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof.

Also provided herein is a method of selecting a subject having cancerfor treatment including administration of a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof, the method comprising determining that the cancer inthe subject is a FGFR-associated cancer, and selecting a subjectdetermined to have a FGFR-associated cancer for treatment includingadministration of a therapeutically effective amount of a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof.

Also provided herein is a method for inhibiting angiogenesis of a cancerin a subject in need thereof, the method comprising administering to thesubject a therapeutically effective amount of a compound of Formula I,or a pharmaceutically acceptable salt or solvate thereof.

Also provided herein is a method for inhibiting metastasis of a cancerin a subject in need thereof, the method comprising administering to thesubject a therapeutically effective amount of a compound of Formula I,or a pharmaceutically acceptable salt or solvate thereof.

Also provided herein is a method of selecting a treatment for a subject,the method comprising selecting a therapeutically effective amount of acompound of Formula I, or a pharmaceutically acceptable salt or solvatethereof, for a subject (i) identified or diagnosed as having aFGFR-associated cancer, (ii) previously administered one or more dosesof a second FGFR inhibitor, and (iii) after administration of the one ormore doses of the second FGFR inhibitor, identified as having about thesame or an elevated level of circulating tumor DNA as compared to areference level of circulating tumor DNA.

Also provided herein is a method of selecting a treatment for a subject,the method comprising selecting a therapeutically effective amount of acompound of Formula I, or a pharmaceutically acceptable salt or solvatethereof, and an additional therapy or therapeutic agent for a subject(i) identified or diagnosed as having a FGFR-associated cancer, (ii)previously administered one or more doses of the compound of Formula I,or a pharmaceutically acceptable salt or solvate thereof, as amonotherapy, and (iii) after administration of the one or more doses ofthe compound of Formula I, or a pharmaceutically acceptable salt orsolvate thereof, identified as having about the same or an elevatedlevel of circulating tumor DNA as compared to a reference level ofcirculating tumor DNA.

Also provided herein is a method of determining efficacy of a treatmentin a subject, the method comprising determining a first level ofcirculating tumor DNA in a biological sample obtained from a subjectidentified or diagnosed as having a FGFR-associated cancer at a firsttime point, administering a treatment comprising one or more doses of acompound of Formula I, or a pharmaceutically acceptable salt or solvatethereof to the subject, after the first time point and before a secondtime point, determining a second level of circulating tumor DNA in abiological sample obtained from the subject at the second time point,and identifying that the treatment is effective in a subject determinedto have a decreased second level of circulating tumor DNA as compared tothe first level of circulating tumor DNA, or identifying the treatmentis not effective in a subject determined to have about the same or anelevated second level of circulating tumor DNA as compared to the firstlevel of circulating tumor DNA.

Also provided herein is a method of determining whether a subject hasdeveloped resistance to a treatment, the method comprising determining afirst level of circulating tumor DNA in a biological sample obtainedfrom a subject identified or diagnosed as having a FGFR-associatedcancer at a first time point, administering a treatment comprising oneor more doses of a compound of Formula I, or a pharmaceuticallyacceptable salt or solvate thereof to the subject, after the first timepoint and before a second time point, determining a second level ofcirculating tumor DNA in a biological sample obtained from the subjectat the second time point, and determining that a subject having adecreased second level of circulating tumor DNA as compared to the firstlevel of circulating tumor DNA has not developed resistance to thetreatment, or determining that a subject having about the same or anelevated second level of circulating tumor DNA as compared to the firstlevel of circulating tumor DNA has developed resistance to thetreatment.

Also provided herein is a process for preparing a compound of Formula Ior a pharmaceutically acceptable salt or solvate thereof.

Also provided herein is a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof obtained by a process of preparingthe compound as defined herein.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Methods and materials aredescribed herein for use in the present invention; other, suitablemethods and materials known in the art can also be used. The materials,methods, and examples are illustrative only and not intended to belimiting. All publications, patent applications, patents, sequences,database entries, and other references mentioned herein are incorporatedby reference in their entirety. In case of conflict, the presentspecification, including definitions, will control.

Other features and advantages of the invention will be apparent from thefollowing detailed description, and from the claims.

DESCRIPTION OF DRAWINGS

FIG. 1 contains amino acid sequences of SEQ ID NOs: 1-8

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, provided herein is a compound of Formula I

and pharmaceutically acceptable salts and solvates thereof, wherein:

R¹ is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl;

Ring A is Ar¹ or hetAr¹;

Ar¹ is phenyl optionally substituted with 1-2 independently selectedhalogen or C1-C6 alkyl;

hetAr¹ is a 5-6 membered heteroaryl ring having 1-3 ring nitrogen atomsand optionally substituted with 1-2 independently selected halogen orC1-C6 alkyl;

Ring B is a 4-6 membered saturated heterocyclic ring wherein X¹ is CH orN and X² is N;

L is C(═O)— or —CH₂—;

Ring C is a 4-6 membered saturated heterocyclic ring wherein X³ is N,wherein said ring is optionally substituted with halogen, CN, OH, C1-C6alkoxy, or C1-C6 alkyl; and

W is a warhead.

In another aspect, provided herein is a compound of Formula I

and pharmaceutically acceptable salts and solvates thereof, wherein:

R¹ is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl;

Ring A is Ar¹ or hetAr¹;

Ar¹ is phenyl optionally substituted with 1-2 independently selectedhalogen or C1-C6 alkyl;

hetAr¹ is a 5-6 membered heteroaryl ring having 1-3 ring nitrogen atomsand optionally substituted with 1-2 independently selected halogen orC1-C6 alkyl;

Ring B is a 4-6 membered saturated heterocyclic ring wherein X¹ is CH orN and X² is N;

L is C(═O)— or —CH₂—;

Ring C is a 4-6 membered saturated heterocyclic ring wherein X³ is N,wherein said ring is optionally substituted with halogen, CN, OH, C1-C6alkoxy, or C1-C6 alkyl;

W is R²R³C═CR⁴C(═O)—, R⁵R⁶NCH₂CH═CHC(═O)—, H₂C═CHSO₂— or R⁷C≡CC(═O)—;

R² is hydrogen;

R³ is hydrogen, CF₃ or Z(C1-C6 alkyl)- wherein Z is H, F, Cl, Br, HO—,C1-C6 alkoxy, or fluoro C1-C6 alkoxy, and

R⁴ is hydrogen, C1-C3 alkyl, fluoro C1-C3 alkyl or halogen,

or R³ and R⁴ together with the carbon atoms to which they are attachedform a 4-8-membered carbocyclic ring;

R⁵ and R⁶ are each independently selected C1-C6 alkyl, or R⁵ and R⁶together with the nitrogen atom to which they are attached form a 5-6membered heterocyclic ring optionally having an additional ringheteroatom which is O, wherein said ring is optionally substituted withhalogen;

R⁷ is hydrogen, C1-C3 alkyl, HO—C1-C3 alkyl or R′R″NCH₂—; and

R′ and R″ are each independently hydrogen or C1-C6 alkyl.

For complex chemical names employed herein, a substituent group istypically named before the group to which it attaches. For example,methoxyethyl comprises an ethyl backbone with a methoxy substituent.

The term “halogen” or “halo” means —F (sometimes referred to herein as“fluoro” or “fluoros”), —Cl, —Br and —I.

The term “alkyl” refers to a hydrocarbon chain that may be a straightchain or branched chain, containing the indicated number of carbonatoms. For example, the term “C1-C6 alkyl” as used herein refers tosaturated linear or branched-chain monovalent hydrocarbon radicals ofone to six carbon atoms. Examples include, but are not limited to,methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl,tert-butyl, 2-methyl-2-propyl, pentyl, neopentyl, and hexyl.

The term “haloalkyl” refers to an alkyl, in which one or more hydrogenatoms is/are replaced with an independently selected halo.

The term “fluoro C1-C6 alkyl” as used herein refers to a C1-C6 alkylradical as defined herein, wherein one to three hydrogen atoms isreplaced with one to three fluoro atoms, respectively. Examples include,but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl,2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-and trifluoroethyl.

The term “alkenyl” as used herein refers to a hydrocarbon chain that maybe a straight chain or branched chain having one or more carbon-carbondouble bonds. The alkenyl moiety contains the indicated number of carbonatoms. For example, C₂₋₆ or C2-C6 indicates that the group may have from2 to 6 (inclusive) carbon atoms in it.

The term “alkynyl” as used herein refers to a hydrocarbon chain that maybe a straight chain or branched chain having one or more carbon-carbontriple bonds. The alkynyl moiety contains the indicated number of carbonatoms. For example, C₂₋₆ or C2-C6 indicates that the group may have from2 to 6 (inclusive) carbon atoms in it.

The term “alkoxy” refers to an —O-alkyl radical (e.g., —OCH₃). Forexample, the term “C1-C6 alkoxy” as used herein refers to saturatedlinear or branched-chain monovalent alkoxy radicals of one to six carbonatoms, wherein the radical is on the oxygen atom. Examples includemethoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy.

The term “haloalkoxy” refers to an —O-haloalkyl radical (e.g., —OCH₃).

The term “cyano C1-C6 alkyl”, as used herein refers to saturated linearor branched-chain monovalent alkyl radicals of one to six or two to sixcarbon atoms, respectively, wherein one of the carbon atoms issubstituted with a cyano group.

The term “cycloalkyl” as used herein includes saturated cyclichydrocarbon groups having 3 to 20 ring carbons, preferably 3 to 16 ringcarbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbonsor 4-8 ring carbons or 3-6 ring carbons, wherein the cycloalkyl groupmay be optionally substituted. Examples of cycloalkyl groups include,without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. Cycloalkyl may include multiple fusedand/or bridged rings. Non-limiting examples of fused/bridged cycloalkylincludes: bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane,bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane,bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane,bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane,bicyclo[2.2.2]octane, and the like. Cycloalkyl also includes spirocyclicrings (e.g., spirocyclic bicycle wherein two rings are connected throughjust one atom). Non-limiting examples of spirocyclic cycloalkyls includespiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane,spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane,spiro[3.6]decane, spiro[5.5]undecane, and the like. The term “C3-C6cycloalkyl” as used herein refers to cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl. The term “4-8 membered cycloalkyl ring” asused herein refers to cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,and cyclooctyl.

The term “cycloalkenyl” as used herein includes partially unsaturatednon-aromatic cyclic hydrocarbon groups having 3 to 20 ring carbons,preferably 3 to 16 ring carbons, and more preferably 3 to 12 ringcarbons or 3-10 ring carbons or 3-6 ring carbons, wherein thecycloalkenyl group may be optionally substituted. Examples ofcycloalkenyl groups include, without limitation, cyclopentenyl,cyclohexenyl, cycloheptenyl, and cyclooctenyl. Cycloalkenyl groups mayhave any degree of saturation provided that none of the rings in thering system are aromatic; and the cycloalkenyl group is not fullysaturated overall. Cycloalkenyl may include multiple fused and/orbridged and/or spirocyclic rings. The term “heterocycloalkenyl” as usedherein refers to a “cycloalkenyl” wherein from 1-4 ring sp³ carbon atomsare replaced by heteroatoms.

The term “aryl” refers to a 6-20 carbon mono-, bi-, tri- or polycyclicgroup wherein at least one ring in the system is aromatic (e.g.,6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromaticring system); and wherein 0, 1, 2, 3, or 4 atoms of each ring may besubstituted by a substituent. Examples of aryl groups include phenyl,naphthyl, tetrahydronaphthyl, and the like.

The term “heteroaryl”, as used herein, means a mono-, bi-, tri- orpolycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10,or 14 ring atoms; and having 6,10, or 14 pi electrons shared in a cyclicarray; wherein at least one ring in the system is aromatic (but does nothave to be a ring which contains a heteroatom, e.g.tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl), and at least onering in the system contains one or more heteroatoms independentlyselected from the group consisting of N, O, and S(O)₀₋₂. Heteroarylgroups can either be unsubstituted or substituted with one or moresubstituents. Examples of heteroaryl include thienyl, pyridinyl, furyl,oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, pyrazolyl,isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl,triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl,benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl,isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl,pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl,quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl,pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine,pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromane,2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole,2,3-dihydrobenzofuran, tetrahydroquinoline,2,3-dihydrobenzo[b][1,4]oxathiine, isoindoline, and others. In someembodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl,pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, andpyrimidinyl.

The term “heterocyclyl” refers to a mon-, bi-, tri-, or polycyclicnonaromatic saturated ring system with 3-16 ring atoms (e.g., 4-8 (e.g.,4-6) membered monocyclic, 7-12 (e.g., 7-11 or 7-10) membered bicyclic,or 11-14 membered tricyclic ring system) having 1-3 heteroatoms ifmonocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclicor polycyclic, said heteroatoms selected from O, N, or S (e.g., carbonatoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S(O)₀₋₂ ifmonocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3atoms of each ring may be substituted by a substituent. Examples ofheterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl,morpholinyl, tetrahydrofuranyl, and the like. Heterocyclyl may includemultiple fused and bridged rings. Non-limiting examples of fused/bridgedheteorocyclyl includes: 2-azabicyclo[1.1.0]butane,2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane,3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane,3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole,3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane,6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane,2-azabicyclo[2.2.2]octane, 3-azabicyclo[3.2.1]octane,2-oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane,2-oxabicyclo[1.1.1]pentane, 3-oxabicyclo[3.1.0]hexane,5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane,3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane,6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane,2-oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, and the like.Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicyclewherein two rings are connected through just one atom). Non-limitingexamples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane,4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane,7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane,1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane,2-oxaspiro[2.2]pentane, 4-oxaspiro[2.5]octane, l-oxaspiro[3.5]nonane,2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane,6-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decane,2,5-dioxaspiro[3.6]decane, 1-oxaspiro[5.5]undecane,3-oxaspiro[5.5]undecane, 3-oxa-9-azaspiro[5.5]undecane and the like.

The term “alkylene” refers to a branched or unbranched divalent alkyl(e.g., —CH₂—).

The term “heterocyclylene” and the like refer to divalent forms of thering system, here divalent heterocyclyl.

The term “oxo” as used herein means an oxygen that is double bonded to acarbon atom or heteroatom, i.e., ═O. For example, a 4-6 memberedheterocyclic ring having 1-2 ring heteroatoms independently selectedfrom N and O and substituted with an oxo may be, for example, apyrrolidinyl ring substituted with oxo (e.g., a pyrrolidinonyl ring),which may be represented by the structure:

The term “compound,” as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted. Compounds herein identified by name or structure asone particular tautomeric form are intended to include other tautomericforms unless otherwise specified.

The term “tautomer” as used herein refers to compounds whose structuresdiffer markedly in arrangement of atoms, but which exist in easy andrapid equilibrium, and it is to be understood that compounds providedherein may be depicted as different tautomers, and when compounds havetautomeric forms, all tautomeric forms are intended to be within thescope of the invention, and the naming of the compounds does not excludeany tautomer. An example of a tautomeric forms includes the followingexample:

It will be appreciated that certain compounds provided herein maycontain one or more centers of asymmetry and may therefore be preparedand isolated in a mixture of isomers such as a racemic mixture, or in anenantiomerically pure form.

Embodiments can include any one or more of the features delineated belowand/or in the claims.

Ring A

In some embodiments, Ring A is hetAr¹.

In certain embodiments (when Ring A is hetAr¹), Ring A is a 5-6 memberedheteroaryl ring having 1-2 ring nitrogen atoms and optionallysubstituted with 1-2 independently selected C1-C6 alkyl.

In certain embodiments, Ring A is a 5-membered heteroaryl ring having1-2 ring nitrogen atoms and optionally substituted with 1-2independently selected C1-C6 alkyl.

In certain embodiments, Ring A is a 5-membered heteroaryl ring having 2ring nitrogen atoms and optionally substituted with 1-2 independentlyselected C1-C6 alkyl.

In certain embodiments, Ring A is pyrazolyl optionally substituted 1-2independently selected C1-C6 alkyl.

As non-limiting examples to the foregoing embodiments, Ring A can beselected from the following:

wherein the asterisk represents point of attachment to Ring B.

In certain embodiments (when Ring A is hetAr¹), Ring A is a 6 memberedheteroaryl ring having 1-2 ring nitrogen atoms and optionallysubstituted with 1-2 independently selected C1-C6 alkyl.

In certain embodiments, Ring A is pyridinyl optionally substituted with1-2 independently selected C1-C6 alkyl.

As non-limiting examples to the foregoing embodiments. Ring A can beselected from the following:

wherein the asterisk represents point of attachment to Ring B.

In some embodiments, Ring A is Ar¹.

In certain embodiments (when Ring A is Ar¹), Ring A is phenyl optionallysubstituted with 1-2 independently selected halogen or C1-C3 alkyl.

In certain of these embodiments, Ring A is phenyl which isunsubstituted.

In certain embodiments (when Ring A is Ar¹), Ring A is:

wherein the asterisk represents point of attachment to Ring B.

Ring B

In some embodiments, Ring B is a 4-6 membered saturated heterocyclicring wherein X¹ is CH; and X² is N.

In certain embodiments, Ring B is a 6-membered saturated heterocyclicring wherein X¹ is CH; and X² is N.

As a non-limiting example of the foregoing embodiments, Ring B can be:

wherein the asterisk represents point of attachment to L.

In certain embodiments, Ring B is a 5-membered saturated heterocyclicring wherein X¹ is CH; and X² is N.

As a non-limiting example of the foregoing embodiments, Ring B can be:

wherein the asterisk represents point of attachment to L.

In certain embodiments, Ring B is a 4-membered saturated heterocyclicring wherein X¹ is CH; and X² is N.

As a non-limiting example of the foregoing embodiments, Ring B can be:

wherein the asterisk represents point of attachment to L.

In some embodiments, B is a 4-6 membered saturated heterocyclic ringwherein X¹ is N; and X² is N.

In certain embodiments, Ring B is a 6-membered saturated heterocyclicring wherein X¹ is N; and X² is N.

As a non-limiting example of the foregoing embodiments, Ring B can be:

wherein the asterisk represents point of attachment to L.

Variable L

In some embodiments, L is C(═O)—.

In some embodiments, L is —CH₂—.

Ring C

In some embodiments, Ring C is a 4 membered saturated heterocyclic ring,wherein said ring is optionally substituted with halogen, CN, OH, orC1-C6 alkoxy.

In certain embodiments of the foregoing, Ring C is selected from thefollowing:

wherein the asterisk indicates the point of attachment to W.

In some embodiments, Ring C is a 5 membered saturated heterocyclic ring,wherein said ring is optionally substituted with halogen, CN, OH, orC1-C6 alkoxy.

In certain embodiments of the foregoing, Ring C is a 5 memberedsaturated heterocyclic ring.

As a non-limiting example of the foregoing embodiments, Ring C can be:

wherein the asterisk indicates the point of attachment to W.

In some embodiments, Ring C is a 6 membered saturated heterocyclic ring,wherein said ring is optionally substituted with halogen, CN, OH, orC1-C6 alkoxy.

In certain embodiments of the foregoing, Ring C is a 6 memberedsaturated heterocyclic ring.

As a non-limiting example of the foregoing embodiments, Ring C can be:

wherein the asterisk indicates the point of attachment to W.

Non-Limiting Combinations of Ring A, Ring B, L, and Ring C

[A]

In some embodiments, Ring A is a 5-membered heteroaryl ring having 1-2ring nitrogen atoms and optionally substituted with 1-2 independentlyselected C1-C6 alkyl; and Ring B is a 4-6 membered saturatedheterocyclic ring, wherein X¹ is CH; and X² is N.

In certain embodiments, Ring A is a pyrazolyl optionally substitutedwith 1-2 independently selected C1-C6 alkyl.

As non-limiting examples of the foregoing embodiments, Ring A can beselected from the following:

wherein the asterisk represents point of attachment to Ring B.

In certain embodiments of [A], Ring B is a 6 membered saturatedheterocyclic ring.

As a non-limiting example of the foregoing embodiments, Ring B can be:

wherein the asterisk represents point of attachment to L.

In certain embodiments of [A], Ring B is a 5 membered saturatedheterocyclic ring.

As a non-limiting example of the foregoing embodiments, Ring B can be:

wherein the asterisk represents point of attachment to L.

In certain embodiments of [A], Ring B is a 4 membered saturatedheterocyclic ring.

As a non-limiting example of the foregoing embodiments, Ring B can be:

wherein the asterisk represents point of attachment to L.

In some embodiments of [A], L is C(═O)—.

In some embodiments of [A], L is —CH₂—.

In some embodiments of [A], Ring C is a 4 membered saturatedheterocyclic ring, wherein said ring is optionally substituted withhalogen, CN, OH, or C1-C6 alkoxy.

In certain embodiments of the foregoing, Ring C is selected from thefollowing:

wherein the asterisk indicates the point of attachment to W.

In some embodiments of [A], Ring C is a 5 membered saturatedheterocyclic ring having one ring nitrogen atom.

In some embodiments of [A], Ring C is a 6 membered saturatedheterocyclic ring having one ring nitrogen atom.

[B]

In some embodiments, Ring A is a 6 membered heteroaryl ring having 1-2ring nitrogen atoms and optionally substituted with 1-2 independentlyselected C1-C6 alkyl; and Ring B is a 6-membered saturated heterocyclicring, wherein X¹ is N; and X² is N.

In certain embodiments, Ring A is pyridinyl optionally substituted with1-2 independently selected C1-C6 alkyl.

As non-limiting examples of the foregoing embodiments, Ring A can beselected from the following:

wherein the asterisk represents point of attachment to Ring B.

In certain embodiments of [B], Ring B is

wherein the asterisk represents point of attachment to L.

In some embodiments of [B], L is C(═O)—.

In some embodiments of [B], Ring C is a 4 membered saturatedheterocyclic ring, wherein said ring is optionally substituted withhalogen, CN, OH, or C1-C6 alkoxy.

In certain embodiments of the foregoing, Ring C is selected from thefollowing:

wherein the asterisk indicates the point of attachment to W.

In some embodiments of [B], Ring C is a 5 membered saturatedheterocyclic ring.

In some embodiments of [B], Ring C is a 6 membered saturatedheterocyclic ring.

[C]

In some embodiments, Ring A is Ar¹; and Ring B is a 6-membered saturatedheterocyclic ring, wherein X¹ is N; and X² is N.

In certain embodiments, Ring A is phenyl optionally substituted with 1-2independently selected halogen or C1-C3 alkyl.

In certain of these embodiments, Ring A is phenyl which isunsubstituted.

In certain embodiments, Ring A is

wherein the asterisk represents point of attachment to Ring B.

In certain embodiments of [C], Ring B is

wherein the asterisk represents point of attachment to L.

In some embodiments of [C], L is C(═O)—.

In some embodiments of [C], Ring C is a 4 membered saturatedheterocyclic ring, wherein said ring is optionally substituted withhalogen, CN, OH, or C1-C6 alkoxy.

In certain embodiments of the foregoing, Ring C is selected from thefollowing:

wherein the asterisk indicates the point of attachment to W.

In some embodiments of [C], Ring C is a 5 membered saturatedheterocyclic ring having one ring nitrogen atom.

In certain embodiments of the foregoing, Ring C is a 6 memberedsaturated heterocyclic ring having one ring nitrogen atom.

Variable R¹

In some embodiments, R¹ is hydrogen.

In some embodiments, R¹ is C2-C4 alkynyl.

In certain embodiments, R¹ is HC≡CCH₂—.

Variable W

In some embodiments, W is a warhead, wherein the warhead is as definedelsewhere herein.

In some embodiments, W is R²R³C═CR⁴C(═O)—.

In certain embodiments (when W is R²R³C═CR⁴C(═O)—), R³ is hydrogen.

In certain embodiments (when W is R²R³C═CR⁴C(═O)—), R⁴ is hydrogen.

As a non-limiting example of the foregoing embodiments, W can beCH₂═CHC(═O)—.

In some embodiments, W is R⁵R⁶NCH₂CH═CHC(═O)—.

In certain embodiments (when W is R⁵R⁶NCH₂CH═CHC(═O)—), each of R⁵ andR⁶ is independently C1-C6 alkyl.

In certain embodiments (when W is R⁵R⁶NCH₂CH═CHC(═O)—), each of R⁵ andR⁶ is independently C1-C3 alkyl.

In certain embodiments (when W is R⁵R⁶NCH₂CH═CHC(═O)—), each of R⁵ andR⁶ is independently methyl.

As a non-limiting example of the foregoing embodiments, W is(CH₃)₂NCH₂CH═CHC(═O)—.

The compounds described herein include one or more “warheads” as part oftheir chemical structure. In Formula I, variable “W” represents awarhead. As used herein, the term “warhead” refers to a moiety havingone or more reactive functional groups that are capable of covalentlybinding (e.g., irreversibly or reversibly; e.g., irreversibly) to one ormore cysteine residues present in an FGFR protein (e.g., FGFR2 orFGFR3), thereby irreversibly or reversibly forming a covalent bondbetween the warhead and the one or more cysteine residues. Withoutwishing to be bound by theory, it is believed that the formation of saidcovalent bond between the warhead and the one or more cysteine residuescan alter one or more properties associated with an FGFR protein; e.g.,can inhibit one or more functions or activities associated with the FGFRprotein.

In some embodiments, the “warhead” is a chemical moiety that is capableof irreversibly forming a covalent bond to one or more cysteine residuespresent in an FGFR protein.

In some embodiments, the “warhead” is a chemical moiety that is capableof reversibly forming a covalent bond to one or more cysteine residuespresent in an FGFR protein.

In some embodiments, the warhead is suitable for covalently binding to akey cysteine residue in the binding domain of a FGFR protein. One ofordinary skill in the art will appreciate that FGFR receptors, mutantsthereof, and fusion proteins thereof have a cysteine residue in thebinding domain. It is believed that proximity of a warhead to thecysteine of interest facilitates covalent modification of that cysteineby the warhead.

In some embodiments, the compounds described herein include one or morewarheads that covalently modify (e.g., reversibly or irreversibly; e.g.,irreversibly) one or more cysteine residues in a kinase insert domain ina FGFR protein (e.g., an FGFR3 protein). In certain embodiments, thecompounds described herein include one or more warheads that covalentlymodify Cys582 in SEQ ID NO: 5.

In some embodiments, the compounds described herein include one or morewarheads that covalently modify (e.g., reversibly or irreversibly; e.g.,irreversibly) one or more cysteine residues in a c-terminal tail of aFGFR protein (e.g., an FGFR2 protein). In certain embodiments, thecompounds described herein include one or more warheads that covalentlymodify Cys808 in SEQ ID NO: 3.

Non-limiting examples of warheads include:

1) α,β unsaturated systems (e.g., L^(W1)-EWG, wherein L^(W1) is alkenylor alkynyl; and EWG is an electron withdrawing group; e.g., Michaelacceptors, e.g., acrylamides, acrylates, vinylsulfones, α,β-unsaturatedketones)

2) Strained non-aromatic heterocycles (e.g., heterocycles having from3-4 ring atoms wherein 1 ring atom is a heteroatom selected from oxygen,nitrogen, and sulfur; e.g., epoxide, aziridine, beta-lactam, and otherstrained systems);

3) Strained carbocyclic systems (e.g., cyclopropyl substituted with oneor more electron-withdrawing groups);

4) Activated ketone (e.g., halomethylketone);

5) Acylating agents (e.g., carbamates, aza-peptides, acyl hydroxamates),phosphonylating agents (e.g., phosphonyl fluorides), or sulfonylationagents (e.g., sulfonyl fluoride);

6) Boronic acids or boronic esters; and

7) Aliphatic organonitrile compounds (e.g., alkyl nitrile, cyanamide, oracyl cyanamide).

Non-limiting examples of “warhead” include W which is a moiety ofFormula A^(W)-W′, wherein

W′ is selected from the group consisting of:

a) L^(W1)-EWG, wherein

L^(W1) is C₂₋₈ alkenyl, C₄₋₁₀ cycloalkenyl, 5-10 memberedheterocycloalkenyl, or C2-s alkynyl, wherein

-EWG is attached to a sp² or sp hybridized carbon of L^(W1), therebyproviding an α,β-unsaturated system;

L^(W1) is optionally substituted with one halo (e.g., F) at the carbonatom attached to -EWG;

the sp² or sp hybridized carbons of L^(W1) which are not attached to EWGare optionally substituted with 1 R^(L1); and

each sp³ hybridized carbon of L^(W1) is optionally substituted with from1-3 substituents each independently selected from halo, OH, C₁₋₆ alkoxy,C₁₋₆ haloalkoxy, NH₂, NH(R^(N)), N(R^(N))₂, and R^(L1); and

EWG is a divalent group selected from: —C(O)—, —S(O)₂—, —C(O)O—,—C(O)NH—, —C(O)NR^(N)—, —S(O)₂NH—, and —S(O)₂NR^(N)—;

b) C₄₋₁₀ cycloalkenyl substituted with from 1-4 substituentsindependently selected from R^(e), C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, and C₁₋₄ thioalkoxy, provided that thecycloalkenyl comprises from 1-4 R^(e);

c) heterocycloalkenyl having from 5-10 ring atoms including from 2-7ring carbon atoms each optionally substituted with 1-2 substituentsindependently selected from R^(e), C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, and C₁₋₄ thioalkoxy, and from 1-3 heteroatomseach independently selected from N, NH, N(R^(N)), N(R^(e)), O, andS(O)₀₋₂, provided that the heterocycloalkenyl comprises one or moreR^(e);

d) heterocyclyl having from 3-4 ring atoms wherein one ring atom is aheteroatom selected from N, NH, N(R^(N)), NC(O)R^(N), NC(O)OR^(N),NS(O)₂R^(N), O, and S; and 2-3 ring atoms are ring carbon atoms eachoptionally substituted with from 1-2 substituents independently selectedfrom R^(e), C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy,and C₁₋₄ thioalkoxy, wherein the heterocyclyl is optionally fused to aring having from 3-8 ring atoms, including from 1-8 ring carbon atomseach of which optionally substituted 1-2 substituents independentlyselected from R^(e), C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, and C₁₋₄ thioalkoxy, and from 0-2 heteroatoms eachindependently selected from N, NH, N(R^(N)), O, and S(O)₀₋₂;

e) C₃₋₄ (e.g., C₃) cycloalkyl substituted with from 1-4 substituentsindependently selected from R^(e), C₁₋₄ alkyl, C₁₋₄ haloalkyl, C1-4alkoxy, C1-4 haloalkoxy, and C1-4 thioalkoxy, provided that thecycloalkyl comprises one or more R^(e);

f) —C(═O)(CH₂)_(n1)X^(w1) wherein X^(w1) is selected from —C(O)R^(c),—S(O)₂R^(c), —C(O)OR^(c), —C(O)NHR^(c), —C(O)NR^(N)R^(c), —S(O)₂NHR^(c),and —S(O)₂NR^(N)R^(c); and n1 is 0, or 1;

g) —C(═O)(CH₂)_(n2)X^(w2) or —C(═O)CH(X^(w2))—R^(c), wherein X^(w2) isselected from OR^(c), SR^(c), S(R^(c))₂, —OP(O)(R^(c))₂, OC(O)R^(c),OC(O)OR^(c), O—NHC(O)R^(c), —OS(O)₂R^(c), —N₂, halo (e.g., F), —CN, and—NO₂; and n2 is 1 or 2;

h) —C(O)NH—N(R^(N))C(O)OR^(c), —C(O)NH—NHC(O)OR^(c),—C(O)NH—N(R^(N))C(O)SR^(c), —C(O)NH—NHC(O)SR^(c), —NHC(O)OR^(c),—N(R^(N))C(O)OR^(c), —NHC(O)SR^(c), —N(R^(N))C(O)SR^(c),—C(O)NH—O(O)OR^(c), —C(O)N(R^(N))—OC(O)OR^(c), —C(O)NH—OC(O)SR^(c), and—C(O)N(R^(N))—OC(O)SR^(c);

i) —P(O)(OR^(c))(OR^(c)), —P(O)(NH₂)(OR^(c)), —P(O)(NHR^(N))(OR^(<)),—P(O)(NR^(N)R^(N))(OR^(<)), —P(O)(OR^(c))F, —S(O)₂OR^(c) and —S(O)₂F;

j) C₂₋₄ alkenyl or C₂₋₄ alkynyl optionally substituted with from 1-2substituents selected from nitro and —CN;

k) —B(OR^(c′))₂;

I) L^(W2)-EWG, wherein

L^(W2) is C₂₋₆ alkenyl, wherein

-EWG is attached to a sp² hybridized carbon of L^(W2), thereby providingan α,β-unsaturated system;

L^(W2) is substituted with one R^(R) at the carbon atom attached to-EWG; and

L^(W2) is further optionally substituted with from 1-3 substituents eachindependently selected from halo, OH, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, NH₂,NH(R^(N)), N(R^(N))₂, and R^(L2); and

EWG is a divalent group selected from: —C(O)—, —S(O)₂—, —C(O)O—,—C(O)NH—, —C(O)NR^(N)—, —S(O)₂NH—, and —S(O)₂NR^(N)—;

m) C₁₋₆ alkyl substituted with one or more CN or —(H)N—CN; and

n) heterocyclyl having from 5-10 ring atoms including from 2-7 ringcarbon atoms, and from 1-3 heteroatoms each independently selected fromN, NH, N(R^(N)), N(R^(e)), O, and wherein the heterocyclyl issubstituted with one or more CN or —(H)N—CN; and the heterocyclyl isfurther optionally substituted with from 1-2 independently selectedR^(e);

A^(W) is a bond or C₁₋₈ alkylene optionally substituted with from 1-2substituents independently selected from OH, C1-4 haloalkyl, C1-4alkoxy, and C1-4 haloalkyl, wherein from 1-4 CH₂ units of the C₁₋₈alkylene are optionally replaced by a group independently selected from:

1) —C(O)—;

2) —S(O)₀₋₂;

3) —NH—, —NR^(N)—;

4) —O—;

5) heterocyclylene having from 5-10 ring atoms, including from 2-7 ringcarbon atoms each optionally substituted with from 1-2 substituents eachindependently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, and C₁₋₄ thioalkoxy, and from 1-3 heteroatomseach independently selected from N, NH, N(R^(N)), O, and S(O)₀₋₂; and

6) C₃₋₈ cycloalkylene optionally substituted with from 1-2 substituentseach independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, and C₁₋₄ thioalkoxy;

wherein:

each occurrence of R^(L1) and R^(L2) is independently selected from:

C₃₋₈ cycloalkyl, wherein the C₃₋₈ cycloalkyl is optionally substitutedwith from 1-4 substituents independently selected from the groupconsisting of halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, CMhaloalkoxy, C₁₋₄ thioalkoxy, NO₂, C(O)OH, C(O)OC₁₋₄ alkyl, C(O)NH₂,C(O)NHR^(N), C(O)NR^(N) ₂ and CN; and

heterocyclyl, wherein the heterocyclyl includes from 3-16 ring atoms,wherein from 1-3 ring atoms are heteroatoms, each independently selectedfrom the group consisting of N, NH, N(R^(N)), NC(O)R^(N), NC(O)OR^(N),NS(O)₂R^(N), O, and S(O)₀₋₂ wherein the heterocyclyl is optionallysubstituted with from 1-4 substituents independently selected from thegroup consisting of halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, C₁₋₄ thioalkoxy, NO₂, C(O)OH, C(O)OC₁₋₄ alkyl, C(O)NH₂,C(O)NHR^(N), C(O)NR^(N) ₂, and CN, provided that the heterocyclyl isattached to L^(W1) or L^(W2) via a carbon atom;

each occurrence of R^(c) is independently selected from:

C₁₋₆ alkyl optionally substituted with from 1-4 substituentsindependently selected from halo and CM alkoxy;

(C₀₋₃ alkylene)-C₃₋₈ cycloalkyl, wherein the C₃₋₈ cycloalkyl isoptionally substituted with from 1-4 substituents independently selectedfrom the group consisting of halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ thioalkoxy, NO₂, C(O)OH, C(O)OC₁₋₄ alkyl,C(O)NH₂, C(O)NHR^(N), C(O)NR % and CN; and

(C₀₋₃ alkylene)-heterocyclyl, wherein the heterocyclyl includes from3-16 ring atoms, wherein from 1-3 ring atoms are heteroatoms, eachindependently selected from the group consisting of N, NH, N(R^(N)),NC(O)R^(N), NC(O)OR^(N), NS(O)₂R^(N), O, and S(O)₀₋₂ wherein theheterocyclyl is optionally substituted with from 1-4 substituentsindependently selected from the group consisting of halo, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ thioalkoxy, NO₂,C(O)OH, C(O)OC₁₋₄ alkyl, C(O)NH₂, C(O)NHR^(N), C(O)NR^(N) ₂ and CN;

each occurrence of R^(c′) is an independently selected R^(c) or H;

each occurrence of R^(e) is independently selected from oxo, NO₂, halo,CN, a suitable leaving group, and -Q¹-Q²,

wherein -Q¹ is a bond or a group selected from:

C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene wherein from one to twoCH₂ units are optionally replaced by a group independently selectedfrom:

—N(R^(N))—, —S(O)₀₋₂—, —O—, —C(O)—, —C(O)O—, —C(O)N(R^(N))—, —C(O)NH—,—S(O)₂N(R^(N))—, and —S(O)₂N(H)—;

Q² is hydrogen or C₁₋₄ alkyl optionally substituted with from 1-2independently selected oxo, halo, NO₂, CN, or a suitable leaving group,provided that when Q¹ is a bond, Q² is not hydrogen or unsubstitutedC₁₋₆ alkyl;

R^(R) is independently selected from the group consisting of:

CN, NO₂, —C(O)R^(c), —S(O)R^(c), —C(O)OR^(c), —C(O)NHR^(c),—C(O)NR^(N)R^(c), —S(O)₂NHR^(c), and —S(O)₂NR^(N)R^(c); and

each R^(N) is independently selected from the group consisting of: C₁₋₄alkyl, C₃₋₁₀ cycloalkyl, and 4-8 membered heterocyclyl, each of which isoptionally substituted with from 1-2 substituents selected from halo,C₁₋₄ alkyl, and C₁₋₄ haloalkyl; or a pair of R^(N) together with thenitrogen atom to which each is attached forms a ring having from 3-8ring atoms, wherein the ring includes: (a) from 1-7 ring carbon atoms,each of which is substituted with from 1-2 substituents independentlyselected from the group consisting of halo and C₁₋₃ alkyl; and (b) from0-3 ring heteroatoms (in addition to the nitrogen atom attached toR^(N)), which are each independently selected from the group consistingof N, N(H), O, and S(O)₀₋₂.

In certain embodiments, R^(e) comprises a suitable leaving group (i.e.,a group that is capable of undergoing nucleophilic displacement). A“suitable leaving group” is a chemical moiety that is readily displacedby an incoming nucleophilic moiety such as the —SH moiety of a cysteine.Suitable leaving groups are well-known in the art (e.g., see, “AdvancedOrganic Chemistry,” Jerry March, 5^(th) Ed., pp. 351-357, John Wiley andSons, N.Y.). Non-limiting examples of such groups include: halo, alkoxy(e.g., OR^(c)), thioalkoxy (e.g., SR^(c)), sulfonyloxy (e.g.,OS(O)R^(c)), acyloxy (e.g., OC(O)R^(c)), and diazonium moieties.Examples of suitable leaving groups include, but are not limited to:—Cl, —Br, —I, —OR^(c), —SR^(c), —S(R^(c))₂, OC(O)R^(c), OC(O)OR^(c),OS(O)₂OR^(c), and OP(O)(OR^(c))₂.

Exemplary Embodiments of Warhead “W”

[1]

In some embodiments of W, W is:

L^(W1)-EWG, wherein

L^(W1) is C₂₋₈ alkenyl, C₄₋₁₀ cycloalkenyl, 5-10 memberedheterocycloalkenyl, or C₂₋₈ alkynyl, wherein

-EWG is attached to a sp² or sp hybridized carbon of L^(W1), therebyproviding an α,β-unsaturated system;

L^(W1) is optionally substituted with one halo (e.g., F) at the carbonatom attached to -EWG;

the sp² or sp hybridized carbons of L^(W1) which are not attached to EWGare optionally substituted with 1 R^(L1); and

each sp³ hybridized carbon of L^(W1) is optionally substituted with from1-3 substituents each independently selected from halo, OH, C₁₋₆ alkoxy,C₁₋₆ haloalkoxy, NH₂, NH(R^(N)), N(R^(N))₂, and R^(L1); and

EWG is a divalent group selected from: —C(O)—, —S(O)₂—, —C(O)O—,—C(O)NH—, —C(O)NR^(N)—, —S(O)₂NH—, and —S(O)₂NR^(N)—.

In some embodiments of [1], EWG is a divalent group selected from:—C(O)—, —S(O)₂—, C(O)O—, —C(O)NH—, and —S(O)₂NH—. As non-limitingexamples of the foregoing, EWG can be —C(O)— or —S(O)₂.

In some embodiments of [1], L^(W1) is C₂₋₃ alkenyl (e.g., C₂ alkenyl)optionally substituted with one halo.

In certain embodiments, L^(W1) is C₂₋₃ alkenyl (e.g., C₂ alkenyl). As anon-limiting example, L^(W1) can be

In certain embodiments, L^(W1) is C₂₋₃ alkenyl (e.g., C₂ alkenyl)substituted with one halo at the carbon atom attached to -EWG. As anon-limiting example, L^(W1) can be

In some embodiments of [1], L^(W1) is C3-8 alkenyl (e.g., C₃ alkenyl)optionally substituted with from 1-3 halo, OH, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, or N(R^(N))₂ at the sp³ hybridized carbons.

In certain embodiments of [1], L^(W1) is C3-8 alkenyl (e.g., C₃ alkenyl)optionally substituted with from 1-3 halo at a sp³ hybridized carbon.

In some embodiments of [1], L^(W1) is C3-8 alkenyl (e.g., C₃ alkenyl)optionally substituted with one OH, C₁₋₆ alkoxy, or C₁₋₆ haloalkoxy at asp³ hybridized carbon.

In some embodiments of [1], L^(W1) is C3-8 alkenyl (e.g., C₃ alkenyl)substituted with one OH, C₁₋₆ alkoxy, or C₁₋₄ haloalkoxy at a sp³hybridized carbon.

In some embodiments of [1], L^(W1) is C3-8 alkenyl (e.g., C₃ alkenyl)optionally substituted with from one N(R^(N))₂ at a sp³ hybridizedcarbon.

In some embodiments of [1], L^(W1) is C3-8 alkenyl (e.g., C₃ alkenyl)substituted with from one N(R^(N))₂ at a sp³ hybridized carbon.

In some embodiments of [1], L^(W1) is C3-8 alkenyl (e.g., C₃ alkenyl)optionally substituted with 1 R^(u) at a sp² hybridized carbon that isnot attached to EWG.

In some embodiments of [1], L^(W1) is C₄₋₁₀ (e.g., C₄₋₆, e.g., C₄)cycloalkenyl. As a non-limiting example, L^(W1) can be

In some embodiments of [1], L^(W1) is C₂₋₈ alkynyl (e.g., C₃₋₈)optionally substituted with from 1-3 halo, OH, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, OH, or N(R^(N))₂ at the sp³ carbons.

In some embodiments of [1], A^(W) is a bond.

In some embodiments of [1], A^(W) is C₁₋₈ alkylene optionallysubstituted with from 1-2 substituents independently selected from OH,C₁₋₄ haloalkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkyl, wherein from 1-4 CH₂units of the C₁₋₈ alkylene are optionally replaced by a groupindependently selected from:

2) —S(O)₀₋₂;

3) —NH—, —NR^(N)—;

4) —O—;

5) heterocyclylene having from 5-10 ring atoms, including from 2-7 ringcarbon atoms each optionally substituted with from 1-2 substituents eachindependently selected from halo, C₁₋₄ alkyl, CM haloalkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkoxy, and C₁₋₄ thioalkoxy, and from 1-3 heteroatoms eachindependently selected from N, NH, N(R^(N)), O, and S(O)₀₋₂; and

6) C₃₋₈ cycloalkylene optionally substituted with from 1-2 substituentseach independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, and C₁₋₄ thioalkoxy.

[1-1]

In some embodiments of [1], A^(W) is a bond (i.e., W is W′).

In some embodiments of [1-1], W or W′ is R²R³C═CR⁴C(═O)—,R⁵R⁶NCH₂CH═CHC(═O)—, H₂C═CHSO₂— or R⁷C≡CC(═O)—; wherein:

R² is hydrogen;

R³ is hydrogen, CF₃ or Z(C1-C6 alkyl)- wherein Z is H, F, Cl, Br, HO—,C1-C6 alkoxy, or fluoro C1-C6 alkoxy, and

R⁴ is hydrogen, C1-C3 alkyl, fluoro C1-C3 alkyl or halogen,

or R³ and R⁴ together with the carbon atoms to which they are attachedform a 4-8-membered carbocyclic ring;

R⁵ and R⁶ are each independently selected C1-C6 alkyl, or R⁵ and R⁶together with the nitrogen atom to which they are attached form a 5-6membered heterocyclic ring optionally having an additional ringheteroatom which is O, wherein said ring is optionally substituted withhalogen;

R⁷ is hydrogen, C1-C3 alkyl, HO—C1-C3 alkyl or R′R″NCH₂—; and

R′ and R″ are each independently hydrogen or C1-C6 alkyl.

In some embodiments of [1-1], W or W′ is R²R³C═CR⁴C(═O)—.

In certain embodiments, R² is hydrogen.

In certain embodiments, R³ is hydrogen.

In certain embodiments, R³ is CF₃.

In certain embodiments, R³ is ZCH₂—, wherein Z is F, Cl, Br, HO— orCH₃O—.

In certain embodiments, R⁴ is H.

In certain embodiments, R⁴ is F.

In certain embodiments, R³ and R⁴ together with the carbon atoms towhich they are attached form a 4-membered carbocyclic ring.

As non-limiting examples to any of the foregoing embodiments (when W isR²R³C═CR⁴C(═O)—), W or W′ can be:

For example, W or W′ can be CH₂═CHC(═O)—.

In some embodiments of [1-1], W or W′ is R⁵R⁶NCH₂CH═CHC(═O)—.

In certain embodiments, each of R⁵ and R⁶ is independently C1-C6 alkyl.

In certain embodiments, each of R⁵ and R⁶ is independently C1-C3 alkyl.

In certain embodiments, each of R⁵ and R⁶ is independently methyl.

As a non-limiting example of the foregoing, W or W′ can be(CH₃)NCH₂CH═CHC(═O)—.

In certain embodiments, R⁵ and R⁶ together with the nitrogen atom towhich they are attached form a 5-6 membered heterocyclic ring optionallyhaving an additional ring heteroatom which is O, wherein said ring isoptionally substituted with halogen.

In certain embodiments, R⁵ and R⁶ together with the nitrogen atom towhich they are attached form a 5-6 membered heterocyclic ring selectedfrom the group consisting of piperidine, morpholine, and pyrrolidine,wherein said ring is optionally substituted with halogen.

As non-limiting examples to any of the foregoing embodiments (when W isR⁵R⁶NCH₂CH═CHC(═O)—), W or W′ can be:

In some embodiments of [1-1], W or W′ is R⁷C≡CC(═O)—.

In certain embodiments, R⁷ is hydrogen or methyl.

In certain embodiments, R⁷ is HOCH₂—.

In certain embodiments, R⁷ is R′R″NCH₂—.

As non-limiting examples to any of the foregoing embodiments (when W isR⁷C≡CC(═O)—), W or W′ can be:

In some embodiments of [1-1], W or W′ is H₂C═CHSO₂—.

Non-limiting examples of W when W is defined according to [1-1] include:

In some embodiments of [1], A^(W) is C₁₋₈ alkylene optionallysubstituted with from 1-2 substituents independently selected from OH,C₁₋₄ haloalkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkyl, wherein from 1-4 CH₂units of the C₁₋₈ alkylene are optionally replaced by a groupindependently selected from:

1) —C(O)—;

2) —S(O)₀₋₂;

3) —NH—, —NR^(N)—;

4) —O—;

5) heterocyclylene having from 5-10 ring atoms, including from 2-7 ringcarbon atoms each optionally substituted with from 1-2 substituents eachindependently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, and C₁₋₄ thioalkoxy, and from 1-3 heteroatomseach independently selected from N, NH, N(R^(N)), O, and S(O)₀₋₂; and

6) C₃₋₈ cycloalkylene optionally substituted with from 1-2 substituentseach independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, and C₁₋₄ thioalkoxy.

In some embodiments of [1-2], one CH₂ unit of A^(W) is replaced by C(O).

In some embodiments of [1-2], one CH₂ unit of A^(W) is replaced by —NH—.

In certain embodiments of the foregoing, one CH₂ unit of A^(W) isreplaced by C(O); and one CH₂ unit of A^(W) is replaced by —NH—.

In some embodiments of [1-2], one CH₂ unit of A^(W) is replaced byS(O)₂.

In some embodiments of [1-2], one CH₂ unit of A^(W) is replaced by —NH—.

In certain embodiments of the foregoing, one CH₂ unit of A^(W) isreplaced by S(O)₂; and one CH₂ unit of A^(W) is replaced by —NH—.

In some embodiments of [1-2], one CH₂ unit of A^(W) is replaced byheterocyclylene having from 5-10 ring atoms, including from 2-7 ringcarbon atoms each optionally substituted with from 1-2 substituents eachindependently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, and C₁₋₄ thioalkoxy, and from 1-3 heteroatomseach independently selected from N, NH, N(R^(N)), O, and S(O)₀₋₂.

In some embodiments of [1-2], W is

wherein EWG and L^(W1) are as defined elsewhere herein.

Non-limiting examples of the foregoing include:

In some embodiments of [1-2], W is

wherein EWG and L^(W1) are as defined elsewhere herein.

Non-limiting examples of the foregoing include:

[2]

In some embodiments of W, W′ is selected from the group consisting of:

C₄₋₁₀ cycloalkenyl substituted with from 1-4 substituents independentlyselected from R^(e), C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, and C₁₋₄ thioalkoxy, provided that the cycloalkenylcomprises one or more R^(e); and

heterocycloalkenyl having from 5-10 ring atoms including from 2-7 ringcarbon atoms each optionally substituted with 1-2 substituentsindependently selected from R^(e), C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, and C₁₋₄ thioalkoxy, and from 1-3 heteroatomseach independently selected from N, NH, N(R^(N)), N(R^(e)), O, andS(O)₀₋₂, provided that the heterocycloalkenyl comprises one or moreR^(e), and the heterocycloalkenyl ring does not include an N—S bond.

In some embodiments of W, W′ is selected from:

C₄₋₁₀ cycloalkenyl (e.g., C₄₋₆) substituted with from 1-4 substituentsindependently selected from R^(e), C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, and C₁₋₄ thioalkoxy, provided that thecycloalkenyl comprises one or more R^(e).

In certain embodiments of the foregoing, one or more R^(e) is oxo.

Non-limiting examples of the foregoing include:

In some embodiments of W, W′ is selected from:

heterocycloalkenyl having from 5-10 ring atoms including from 2-7 ringcarbon atoms each optionally substituted with 1-2 substituentsindependently selected from R^(e), C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, and C₁₋₄ thioalkoxy, and from 1-3 heteroatomseach independently selected from N, NH, N(R^(N)), N(R^(e)), O, andS(O)₀₋₂, provided that the heterocycloalkenyl comprises one or moreR^(e), and the heterocycloalkenyl ring does not include an N—S bond.

In certain embodiments of the foregoing, one or more R^(e) is oxo,wherein one or more oxo is conjugated to a C═C double bond.

Non-limiting examples of the foregoing include:

In some embodiments of [2], A^(W) is a bond.

In some embodiments of [2], A^(W) is C₁₋₈ alkylene optionallysubstituted with from 1-2 substituents independently selected from OH,C₁₋₄ haloalkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkyl, wherein from 1-4 CH₂units of the C₁₋₈ alkylene are optionally replaced by a groupindependently selected from:

1) —C(O)—;

2) —S(O)₀₋₂;

3) —NH—, —NR^(N)—;

4) —O—;

5) heterocyclylene having from 5-10 ring atoms, including from 2-7 ringcarbon atoms each optionally substituted with from 1-2 substituents eachindependently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, and C₁₋₄ thioalkoxy, and from 1-3 heteroatomseach independently selected from N, NH, N(R^(N)), O, and S(O)₀₋₂; and

6) C₃₋₈ cycloalkylene optionally substituted with from 1-2 substituentseach independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, and C₁₋₄ thioalkoxy.

In certain embodiments of the foregoing, A^(W) is C₁₋₆ alkylene whereinfrom 1-2 CH₂ are optionally replaced by a group independently selectedfrom:

3) —NH—, —NR^(N)—; and

4) —O—.

In certain embodiments, A^(W) is a C₁₋₆ alkylene.

Non-limiting examples of W when W is as defined for [2] include:

[3]

In some embodiments of W, W′ is selected from:

heterocyclyl having from 3-4 ring atoms wherein one ring atom is aheteroatom selected from N, NH, N(R^(N)), NC(O)R^(N), NC(O)OR^(N),NS(O)₂R^(N), O, and S; and 2-3 ring atoms are ring carbon atoms eachoptionally substituted with from 1-2 substituents independently selectedfrom R^(e), C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy,and C₁₋₄ thioalkoxy, wherein the heterocyclyl is optionally fused to aring including from 3-8 ring atoms including from 1-8 ring carbon atomseach of which optionally substituted 1-2 substituents independentlyselected from R^(e), C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, and C₁₋₄ thioalkoxy, and from 0-2 heteroatoms eachindependently selected from N, NH, N(R^(N)), O, and S(O)₀₋₂.

In some embodiments of W, W′ is selected from:

heterocyclyl having from 3-4 ring atoms wherein one ring atom is aheteroatom selected from N, NH, N(R^(N)), NC(O)R^(N), NC(O)OR^(N),NS(O)₂R^(N), O, and S; and 2-3 ring atoms are ring carbon atoms eachoptionally substituted with from 1-2 substituents independently selectedfrom R^(e), C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy,and C₁₋₄ thioalkoxy.

In some embodiments of W, W′ is selected from:

heterocyclyl having from 3-4 ring atoms wherein one ring atom is aheteroatom selected from N, NH, N(R^(N)), NC(O)R^(N), NC(O)OR^(N), and O(e.g., O); and 2-3 ring atoms are ring carbon atoms each optionallysubstituted with from 1-2 substituents independently selected fromR^(e), C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, andC₁₋₄ thioalkoxy.

In some embodiments of W, W′ is selected from:

heterocyclyl having from 3 ring atoms wherein one ring atom is aheteroatom selected O; and 2 ring atoms are ring carbon atoms eachoptionally substituted with from 1-2 substituents independently selectedfrom R^(e), C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy,and C₁₋₄ thioalkoxy.

Non-limiting examples of the foregoing include:

In some embodiments of [3], A^(W) is a bond.

In some embodiments of [3], A^(W) is C₁₋₈ alkylene optionallysubstituted with from 1-2 substituents independently selected from OH,C₁₋₄ haloalkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkyl, wherein from 1-4 CH₂units of the C₁₋₈alkylene are optionally replaced by a groupindependently selected from:

1) —C(O)—;

2) —S(O)₀₋₂;

3) —NH—, —NR^(N)—;

4) —O—;

5) heterocyclylene having from 5-10 ring atoms, including from 2-7 ringcarbon atoms each optionally substituted with from 1-2 substituents eachindependently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, and C₁₋₄ thioalkoxy, and from 1-3 heteroatomseach independently selected from N, NH, N(R^(N)), O, and S(O)₀₋₂; and

6) C₃₋₈ cycloalkylene optionally substituted with from 1-2 substituentseach independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, and C₁₋₄ thioalkoxy.

In certain embodiments of the foregoing, A^(W) is C₁₋₄ alkylene whereinfrom 1-2 CH₂ are optionally replaced by a group independently selectedfrom:

1) —C(O)—;

2) —S(O)₀₋₂;

3) —NH—, —NR^(N)—; and

4) —O—.

In certain embodiments of the foregoing, A^(W) is C₁₋₄ alkylene whereinfrom 1-2 CH₂ are optionally replaced by a group independently selectedfrom:

3) —NH—, —NR^(N)—; and

4) —O—.

In certain embodiments, A^(W) is a C₁₋₄ alkylene.

Non-limiting examples of W when W is defined according to [3] include:

[4]

In some embodiments of W, W′ is selected from:

C₃₋₈ (e.g., C₃) cycloalkyl substituted with from 1-4 substituentsindependently selected from R^(e), C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, and C₁₋₄ thioalkoxy, provided that thecycloalkyl comprises one or more R^(e).

In certain embodiments of the foregoing, W′ is selected from:

cyclopropyl substituted with from 1-4 substituents independentlyselected from R^(e), C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, and C₁₋₄ thioalkoxy, provided that the cyclopropyl comprisesone or more R^(e).

In certain embodiments of the foregoing, one R^(e) is —CN.

In certain embodiments, one R^(e) is -Q¹-Q², wherein Q¹ is C₁₋₄ alkylenewherein one CH₂ unit is replaced by C(O), C(O)NH, or C(O)O.

Non-limiting examples of the foregoing include:

In some embodiments of [4], A^(W) is a bond.

In some embodiments of [4], A^(W) is C₁₋₈ alkylene optionallysubstituted with from 1-2 substituents independently selected from OH,C₁₋₄ haloalkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkyl, wherein from 1-4 CH₂units of the C₁₋₈ alkylene are optionally replaced by a groupindependently selected from:

1) —C(O)—;

2) —S(O)₀₋₂;

3) —NH—, —NR^(N)—;

4) —O—;

5) heterocyclylene having from 5-10 ring atoms, including from 2-7 ringcarbon atoms each optionally substituted with from 1-2 substituents eachindependently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, and C₁₋₄ thioalkoxy, and from 1-3 heteroatomseach independently selected from N, NH, N(R^(N)), O, and S(O)₀₋₂; and

6) C₃₋₈ cycloalkylene optionally substituted with from 1-2 substituentseach independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, and C₁₋₄ thioalkoxy.

In certain embodiments of the foregoing, A^(W) is C₁₋₄ alkylene whereinfrom 1-2 CH₂ are optionally replaced by a group independently selectedfrom:

1) —C(O)—;

2) —S(O)₀₋₂;

3) —NH—, —NR^(N)—; and

4) —O—.

In certain embodiments, A^(W) is a C₁₋₄ alkylene.

Non-limiting examples of W when W is as defined according to [4]include:

[5]

In some embodiments of W, W′ is selected from:

—C(═O)(CH₂)_(n1)X^(w1) wherein X^(w1) is selected from —C(O)R^(c),—S(O)₂R^(c), —C(O)OR^(c), —C(O)NHR^(c), —C(O)NR^(N)R^(c), —S(O)₂NHR^(c),and —S(O)₂NR^(N)R^(c); and n1 is 0, or 1 (e.g., 0); and

—C(═O)(CH₂)_(n2)X^(w2) or —C(═O)CH(X^(w2))—R^(c), wherein X^(w2) isselected from OR^(c), SR^(c), S(R^(c))₂, —OP(O)(R^(c))₂, OC(O)R^(c),OC(O)OR^(c), O—NHC(O)R^(e), —OS(O)₂R^(c), —N₂, halo (e.g., F), —CN, and—NO₂; and n2 is 1 or 2 (e.g., 1).

In some embodiments of [5], A^(W) is a bond.

In some embodiments of [5], A^(W) is C₁₋₈ alkylene optionallysubstituted with from 1-2 substituents independently selected from OH,C₁₋₄ haloalkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkyl, wherein from 1-4 CH₂units of the C₁₋₈ alkylene are optionally replaced by a groupindependently selected from:

1) —C(O)—;

2) —S(O)₀₋₂;

3) —NH—, —NR^(N)—;

4) —O—;

5) heterocyclylene having from 5-10 ring atoms, including from 2-7 ringcarbon atoms each optionally substituted with from 1-2 substituents eachindependently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, and C₁₋₄ thioalkoxy, and from 1-3 heteroatomseach independently selected from N, NH, N(R^(N)), O, and S(O)₀₋₂; and

6) C₃₋₈ cycloalkylene optionally substituted with from 1-2 substituentseach independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, and C₁₋₄ thioalkoxy.

In certain embodiments of the foregoing, A^(W) is C₁₋₄ alkylene whereinfrom 1-2 CH₂ are optionally replaced by a group independently selectedfrom:

1) —C(O)—;

2) —S(O)₀₋₂;

3) —NH—, —NR^(N)—; and

4) —O—.

In certain embodiments of the foregoing, A^(W) is C₁₋₄ alkylene.

Non-limiting examples of W (when W is as defined according to [5])include:

[6]

In some embodiments of W, W′ is selected from:

—C(O)NH—N(R^(N))C(O)OR^(c), —C(O)NH—NHC(O)OR^(c),—C(O)NH—N(R^(N))C(O)SR^(c), —C(O)NH—NH(O)SR^(c), —NHC(O)OR^(c),—N(R^(N))C(O)OR^(c), —NHC(O)SR^(c), —N(R^(N))C(O)SR^(c),—C(O)NH—O(O)OR^(c), —C(O)N(R^(N))—OC(O)OR^(c), —C(O)NH—OC(O)SR^(c), and—C(O)N(R^(N))—OC(O)SR^(c); and

—P(O)(OR^(c))(OR^(c)), —P(O)(NH₂)(OR^(c)), —P(O)(NHR^(N))(OR^(c)),—P(O)(NR^(N)R^(N))(OR^(c)), —P(O)(OR^(c))F, —S(O)₂R^(c) and —S(O)₂F.

In some embodiments of [6], A^(W) is a bond.

In some embodiments of [6], A^(W) is C₁₋₈ alkylene optionallysubstituted with from 1-2 substituents independently selected from OH,C₁₋₄ haloalkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkyl, wherein from 1-4 CH₂units of the C₁₋₈ alkylene are optionally replaced by a groupindependently selected from:

1) —C(O)—;

2) —S(O)₀₋₂;

3) —NH—, —NR^(N)—;

4) —O—;

5) heterocyclylene having from 5-10 ring atoms, including from 2-7 ringcarbon atoms each optionally substituted with from 1-2 substituents eachindependently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, and C₁₋₄ thioalkoxy, and from 1-3 heteroatomseach independently selected from N, NH, N(R^(N)), O, and S(O)₀₋₂; and

6) C₃₋₈ cycloalkylene optionally substituted with from 1-2 substituentseach independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, and C₁₋₄ thioalkoxy.

In certain embodiments of the foregoing, A^(W) is C₁₋₄ alkylene whereinfrom 1-2 CH₂ are optionally replaced by a group independently selectedfrom:

1) —C(O)—;

2) —S(O)₀₋₂;

3) —NH—, —NR^(N)—; and

4) —O—.

In certain embodiments, A^(W) is a C₁₋₄ alkylene (e.g., CH₂).

[7]

In some embodiments of W, W′ is selected from:

C₁₋₄ alkenyl or C₂₋₄ alkynyl optionally substituted with from 1-2substituents selected from nitro and —CN;

In certain embodiments of W, W′ is selected from:

C₂ alkenyl and C₂ alkynyl.

In some embodiments of W, W′ is selected from:

C₂ alkenyl substituted with from 1 substituent selected from nitro and—CN;

Non-limiting examples of the foregoing include:

In some embodiments of [7], A^(W) is a bond.

In some embodiments of [7], A^(W) is C₁₋₈ alkylene optionallysubstituted with from 1-2 substituents independently selected from OH,C₁₋₄ haloalkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkyl, wherein from 1-4 CH₂units of the C₁₋₈ alkylene are optionally replaced by a groupindependently selected from:

1) —C(O)—;

2) —S(O)₀₋₂;

3) —NH—, —NR^(N)—;

4) —O—;

5) heterocyclylene having from 5-10 ring atoms, including from 2-7 ringcarbon atoms each optionally substituted with from 1-2 substituents eachindependently selected from halo, C₁₋₄ alkyl, CM haloalkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkoxy, and C₁₋₄ thioalkoxy, and from 1-3 heteroatoms eachindependently selected from N, NH, N(R^(N)), O, and S(O)₀₋₂; and

6) C₃₋₈ cycloalkylene optionally substituted with from 1-2 substituentseach independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, and C₁₋₄ thioalkoxy;

In certain embodiments of the foregoing, A^(W) is C₁₋₄ alkylene whereinfrom 1-2 CH₂ are optionally replaced by a group independently selectedfrom:

1) —C(O)—;

2) —S(O)₀₋₂;

3) —NH—, —NR^(N)—; and

4) —O—.

In certain embodiments of the foregoing, A^(W) is C₁₋₄ alkylene whereinfrom 1-2 CH₂ are optionally replaced by a group independently selectedfrom:

3) —NH—, —NR^(N)—; and

4) —O—.

In certain embodiments, A^(W) is a C₁₋₄ alkylene optionally substitutedwith one OH.

In certain embodiments, A^(W) is a C₁₋₄ alkylene (e.g., CH₂).

Non-limiting examples of W when W is as defined for [7] include:

[8]

In some embodiments of W, W′ is selected from: —B(OR^(c′))₂.

Non-limiting examples of the foregoing include: —B(OH)₂.

In some embodiments of [8], A^(W) is a bond.

In some embodiments of [8], A^(W) is C₁₋₈ alkylene optionallysubstituted with from 1-2 substituents independently selected from OH,C₁₋₄ haloalkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkyl, wherein from 1-4 CH₂units of the C₁₋₈ alkylene are optionally replaced by a groupindependently selected from:

1) —C(O)—;

2) —S(O)₀₋₂;

3) —NH—, —NR^(N)—;

4) —O—;

5) heterocyclylene having from 5-10 ring atoms, including from 2-7 ringcarbon atoms each optionally substituted with from 1-2 substituents eachindependently selected from halo, C₁₋₄ alkyl, CM haloalkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkoxy, and C₁₋₄ thioalkoxy, and from 1-3 heteroatoms eachindependently selected from N, NH, N(R^(N)), O, and S(O)₀₋₂; and

6) C₃₋₈ cycloalkylene optionally substituted with from 1-2 substituentseach independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, and C₁₋₄ thioalkoxy.

In certain embodiments of the foregoing, A^(W) is C₁₋₄ alkyleneoptionally substituted with from 1-2 substituents independently selectedfrom OH, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkyl, wherein from1-4 CH₂ units of the C₁₋₄ alkylene are optionally replaced by a groupindependently selected from:

1) —C(O)—;

2) —S(O)₀₋₂;

3) —NH—, —NR^(N)—; and

4) —O—.

In certain embodiments of the foregoing, A^(W) is C₁₋₄ alkylene, whereinfrom 1-2 CH₂ units of the C₁₋₈ alkylene are optionally replaced by agroup independently selected from:

1) C(═O)

3) —NH—, —NR^(N)—; and

4) —O—.

In certain embodiments, A^(W) is a C₁₋₆ alkylene (e.g., CH₂).

Non-limiting examples of W when W is as defined for [8] include:

[9]

In some embodiments of W, W′ is selected from:

L^(W2)-EWG, wherein

L^(W2) is C₂₋₆ alkenyl, wherein

-EWG is attached to a sp² hybridized carbon of L^(W2), thereby providingan α,β-unsaturated system;

L^(W2) is substituted with one R″ at the carbon atom attached -EWG; and

L^(W2) is further optionally substituted with from 1-3 substituents eachindependently selected from halo, OH, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, NH₂,NH(R^(N)), N(R^(N))₂, and R^(L2); and

EWG is a divalent group selected from: —C(O)—, —S(O)₂—, —C(O)O—,—C(O)NH—, —C(O)NR^(N)—, —S(O)₂NH—, and —S(O)₂NR^(N)—.

In certain embodiments of the foregoing, L^(W2) is C₂₋₁ alkenyl, whereinL*² is substituted with one R^(R) at a carbon adjacent to EWG.

In certain embodiments of the foregoing, R^(R) is independently selectedfrom the group consisting of:

CN, NO₂, —C(O)R^(c), —S(O)₂R^(c), —O(O)OR^(c), —C(O)NHR^(c),—C(O)NR^(N)R^(c), —S(O)₂NHR^(c), and —S(O)₂NR^(N)R^(c).

As a non-limiting example of the foregoing, R^(R) can be —CN.

Non-limiting examples of the foregoing include:

In some embodiments of [9], A^(W) is a bond.

In some embodiments of [9], A^(W) is C₁₋₈ alkylene optionallysubstituted with from 1-2 substituents independently selected from OH,C₁₋₄ haloalkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkyl, wherein from 1-4 CH₂units of the C₁₋₈alkylene are optionally replaced by a groupindependently selected from:

1) —C(O)—;

2) —S(O)₀₋₂;

3) —NH—, —NR^(N)—;

4) —O—;

5) heterocyclylene having from 5-10 ring atoms, including from 2-7 ringcarbon atoms each optionally substituted with from 1-2 substituents eachindependently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, and C₁₋₄ thioalkoxy, and from 1-3 heteroatomseach independently selected from N, NH, N(R^(N)), O, and S(O)₀₋₂; and

6) C₃₋₈ cycloalkylene optionally substituted with from 1-2 substituentseach independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, and C₁₋₄ thioalkoxy.

In certain embodiments of the foregoing, A^(W) is C₁₋₆ alkylene whereinfrom 1-2 CH₂ are optionally replaced by a group independently selectedfrom:

1) —C(O)—;

2) —S(O)₀₋₂;

3) —NH—, —NR^(N)—; and

4) —O—.

In certain embodiments of the foregoing, A^(W) is C₁₋₆ alkylene whereinfrom 1-2 CH₂ are optionally replaced by a group independently selectedfrom:

3) —NH—, —NR^(N)—; and

4) —O—.

In certain embodiments, A^(W) is a C₁₋₆ alkylene (e.g., CH₂).

Non-limiting examples of W when W is as defined according to [9]include:

[10]

In some embodiments of W, W′ is selected from:

C₁₋₆ alkyl substituted with one or more CN or —(H)N—CN; and

heterocyclyl having from 5-10 ring atoms including from 2-7 ring carbonatoms, and from 1-3 heteroatoms each independently selected from N, NH,N(R^(N)), N(R^(e)), O, and S(O)₀₋₂, wherein the heterocyclyl issubstituted with one or more CN or —(H)N—CN; and the heterocyclyl isfurther optionally substituted with from 1-2 R^(e).

In some embodiments of W, W′ is selected from:

C₁₋₄ alkyl substituted with one CN or —(H)N—CN; and

heterocyclyl having from 5-10 ring atoms including from 2-7 ring carbonatoms, and from 1-3 heteroatoms each independently selected from N, NH,N(R^(N)), N(R^(e)), O, and S(O)₀₋₂, wherein the heterocyclyl issubstituted with one CN or —(H)N—CN; and the heterocyclyl is furtheroptionally substituted with from 1-2 R^(e).

In some embodiments of [10], A^(W) is a bond.

In some embodiments of [10], A^(W) is C₁₋₈ alkylene optionallysubstituted with from 1-2 substituents independently selected from OH,C₁₋₄ haloalkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkyl, wherein from 1-4 CH₂units of the C₁₋₈ alkylene are optionally replaced by a groupindependently selected from:

1) —C(O)—;

2) —S(O)₀₋₂;

3) —NH—, —NR^(N)—;

4) —O—;

5) heterocyclylene having from 5-10 ring atoms, including from 2-7 ringcarbon atoms each optionally substituted with from 1-2 substituents eachindependently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, and C₁₋₄ thioalkoxy, and from 1-3 heteroatomseach independently selected from N, NH, N(R^(N)), O, and S(O)₀₋₂; and

6) C₃₋₈ cycloalkylene optionally substituted with from 1-2 substituentseach independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, and C₁₋₄ thioalkoxy.

In certain embodiments of the foregoing, A^(W) is C₁₋₆ alkylene whereinfrom 1-2 CH₂ are optionally replaced by a group independently selectedfrom:

1) —C(O)—;

2) —S(O)₀₋₂;

3) —NH—, —NR^(N)—; and

4) —O—.

In certain embodiments of [10], one CH₂ unit of A^(W) is replaced by aC(O).

In certain embodiments of [10], one CH₂ unit of A^(W) is replaced by—NH— or —NR^(N).

In some embodiments of [10], A^(W) is a C₁₋₆ alkylene (e.g., CH₂).

Non-limiting examples of W when W is as defined according to [10]include the following:

Further non-limiting examples of “warheads” include those described inU.S. Patent Application Publication No. 2011/0230476 and those describedin Chem. Rev. 2002, 102, 4639, each of which is incorporated byreference herein in its entirety.

Other non-limiting examples of “warhead” include those described inCurr. Opin. Chem. Biol. 2016, 34, 110-116, which is incorporated byreference herein in its entirety.

The compounds of Formula I include pharmaceutically acceptable saltsthereof. In addition, the compounds of Formula I also include othersalts of such compounds which are not necessarily pharmaceuticallyacceptable salts, and which may be useful as intermediates for preparingand/or purifying compounds of Formula I and/or for separatingenantiomers of compounds of Formula I. Non-limiting examples ofpharmaceutically acceptable salts of compounds of Formula I includetrifluoroacetic acid salts. In one embodiment, compounds of Formula Iinclude trifluoroacetic acid and dihydrochloride salts.

It will further be appreciated that the compounds of Formula I or theirsalts may be isolated in the form of solvates, and accordingly that anysuch solvate is included within the scope of the present invention. Forexample, compounds of Formula I and salts thereof can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like.

In some embodiments, the compounds of Formula I include the compounds ofExamples 1-30 and stereoisomers and pharmaceutically acceptable saltsand solvates thereof. In one embodiment, the compounds of Examples 1-30are in the free base form.

The term “pharmaceutically acceptable” indicates that the compound, orsalt or composition thereof is compatible chemically and/ortoxicologically with the other ingredients comprising a formulationand/or the patient being treated therewith.

Compounds provided herein may also contain unnatural proportions ofatomic isotopes at one or more of the atoms that constitute suchcompounds. That is, an atom, in particular when mentioned in relation toa compound according to Formula I, comprises all isotopes and isotopicmixtures of that atom, either naturally occurring or syntheticallyproduced, either with natural abundance or in an isotopically enrichedform. For example, when hydrogen is mentioned, it is understood to referto ¹H, ²H, ³H or mixtures thereof; when carbon is mentioned, it isunderstood to refer to ¹¹C, ¹²C, ¹³C, ¹⁴C or mixtures thereof; whennitrogen is mentioned, it is understood to refer to ¹³N, ¹⁴N, ¹⁵N ormixtures thereof; when oxygen is mentioned, it is understood to refer to¹⁴O, ¹⁵O, ¹⁶O, ¹⁷O, ¹⁸O or mixtures thereof; and when fluoro ismentioned, it is understood to refer to ¹⁸F, ¹⁹F or mixtures thereof.The compounds provided herein therefore also comprise compounds with oneor more isotopes of one or more atoms, and mixtures thereof, includingradioactive compounds, wherein one or more non-radioactive atoms hasbeen replaced by one of its radioactive enriched isotopes. Radiolabeledcompounds are useful as therapeutic agents, e.g., cancer therapeuticagents, research reagents, e.g., assay reagents, and diagnostic agents,e.g., in vivo imaging agents. All isotopic variations of the compoundsprovided herein, whether radioactive or not, are intended to beencompassed within the scope of the present invention.

For illustrative purposes, Schemes 1-4 show general methods forpreparing the compounds provided herein as well as key intermediates.For a more detailed description of the individual reaction steps, seethe Examples section below. Those skilled in the art will appreciatethat other synthetic routes may be used to synthesize the inventivecompounds. Although specific starting materials and reagents aredepicted in the Schemes and discussed below, other starting materialsand reagents can be easily substituted to provide a variety ofderivatives and/or reaction conditions. In addition, many of thecompounds prepared by the methods described below can be furthermodified in light of this disclosure using conventional chemistry wellknown to those skilled in the art.

Scheme 1 shows a general scheme for the synthesis of a compound ofFormula I (shown as compound 3 in Scheme 1), wherein R¹, Ring A, X¹, X²,Ring B, L, X³, Ring C, and W are as defined for Formula I. Compound 1,wherein R¹, Ring A, X¹, X², Ring B, L, X³, and Ring C are as defined forFormula I; and Pg¹ is an amino protecting group (e.g., Boc) (compound 1optionally comprises one or more hydroxy or amino protecting groups),can be subjected to deprotection conditions (e.g., acidic conditionssuch as trifluoroacetic acid) to afford compound 2 which can then beconverted into compound 3, a compound of Formula I wherein W is asdefined for Formula I.

As a non-limiting example for the transformation of 2 into 3, when W isR²R³C═CR⁴C(═O)— or R⁵R⁶NCH₂CH═CHC(═O)— wherein R², R³, R⁴, R⁵, and R⁶are as defined for Formula I, compound 2 can be reacted with a reagentof formula R²R³C═CR⁴C(═O)OH or R⁵R⁶NCH₂CH═CHC(═O)OH in the presence ofone or more amide coupling reagents (e.g., HATU).

Non-limiting examples for the preparation of compound 1 are described inSchemes 2-3 below.

Scheme 2 shows a general method for the synthesis of compound 1 (shownas compound 8 in Scheme 2) wherein Ring A, X¹, X², L, Ring C, X³ are asdefined for Formula I; and Pg¹ is an amino protecting group (e.g., Boc).Compound 4 wherein X is halo (e.g., C1) can be coupled (e.g., Suzukicoupling with a palladium catalyst) with a compound of formula 5 whereinRing A, X¹, X², and Ring B are as defined for Formula I; Pg¹ is an aminoprotecting group; and each R^(B) is independently H or (1-6C)alkyl, oreach R^(B) together with the atoms to which they are connected form a5-6 membered ring optionally substituted with 1-4 substituents selectedfrom (C1-C3 alkyl) to provide compound 6. The amino protecting group on6 can be removed (e.g., under acidic conditions such as trifluoroaceticacid) to provide compound 7. Compound 7 may be converted into compound8, wherein X³ and Ring C are as defined for Formula I; and Pg¹ is anamino protecting group.

As a non-limiting example for the transformation of 7 into 8, when L isC(═O), compound 7 can be coupled with a reagent of formula:

wherein X³ and Ring C are as defined for Formula I; and Pg¹ is an aminoprotecting group in the presence of one or more amide coupling reagents(e.g., HATU).

As another non-limiting example for the transformation of 7 into 8, whenL is CH₂, compound 7 can be coupled with a reagent of formula:

wherein X³ and Ring C are as defined for Formula I; and Pg¹ is an aminoprotecting group under reductive amination conditions.

Scheme 3 shows another general method for the synthesis of compound 1(shown as compound 11 in Scheme 3), wherein Ring A, X¹, X², Ring B, L,X³, and Ring C are as defined for Formula I; R¹ is C1-C4 alkyl, C2-C4alkenyl, or C2-C4 alkynyl; and Pg¹ is an amino protecting group.Compound 10 wherein Ring A, X¹, X², Ring B, L, X³, Ring C, and Pg¹ areas defined for Scheme 2 can be prepared according to Scheme 2. Anyhydroxy and/or amino functional groups on compound 11 can be optionallyprotected if present. Compound 10 (or protected analog thereof) can beconverted into compound 11 upon reaction with a reagent of formula R²-Lgwherein Lg is a leaving atom (e.g., halo, e.g., Br or I) or leavinggroup (e.g., OTf), wherein R¹ is C1-C4 alkyl, C2-C4 alkenyl, or C2-C4alkynyl.

Scheme 4 shows general methods for synthesizing compound 5 (Scheme 2)wherein Ring A, X¹, X², and Ring B are as defined for Formula I; Pg¹ isan amino protecting group; and each R^(B) is independently H or(1-6C)alkyl, or each R^(B) together with the atoms to which they areconnected form a 5-6 membered ring optionally substituted with 1-4substituents selected from (C1-C3 alkyl). Compound 11 wherein X¹ is N;X² and Ring B are as defined for Formula I; and Pg¹ is an aminoprotecting group can be coupled (e.g., via an S_(N)Ar reaction) withcompound 12 wherein X^(L) is a halo (e.g., Br, Cl); and Lg is a leavingatom (e.g., halo, e.g., F, C1) or leaving group (e.g., OTf) to providecompound 13. Compound 13 may be converted into compound 5 (e.g., throughMiyaura borylation; or through sequential metal-halogen exchange andtrapping with a boron-electrophile such as triisopropyl borate) whereinX¹ is N. Alternatively, 13 wherein X¹ is CH; and Ring A is hetAr¹ can beafforded through the coupling of 15 wherein X¹ is CH; X² and Ring B areas defined for Formula I; Pg¹ is an amino protecting group; and Lg is aleaving atom (e.g., halo, e.g., Br, I) or leaving group (e.g., OMs, OTf)with compound 16 wherein Ring A is hetAr¹. Compound 13 wherein X¹ is CH;and Ring A is hetAr¹ can then be converted into compound 5 (e.g.,through Miyaura borylation; or through sequential metal-halogen exchangeand trapping with a boron-electrophile such as triisopropyl borate)wherein X¹ is CH; and Ring A is hetAr¹.

Accordingly, further provided herein is a process for preparing acompound of Formula I, comprising:

for a compound of Formula I wherein R¹, Ring A, X¹, X², Ring B, L, RingC, and W are as defined for Formula I, functionalizing a compound havingthe formula:

wherein R¹, Ring A, X¹, X², Ring B, L, and Ring C are as defined forFormula I; and

removing any additional protecting groups if present and optionallypreparing a pharmaceutically acceptable salt thereof.

The term “amino protecting group” as used herein refers to a derivativeof the groups commonly employed to block or protect an amino group whilereactions are carried out on other functional groups on the compound.Examples of suitable protecting groups for use in any of the processesdescribed herein include carbamates, amides, alkyl and aryl groups,imines, as well as many N-heteroatom derivatives that can be removed toregenerate the desired amine group. Non-limiting examples of aminoprotecting groups are acetyl, trifluoroacetyl, t-butyloxycarbonyl(“Boc”), benzyloxycarbonyl (“CBz”) and 9-fluorenylmethyleneoxycarbonyl(“Fmoc”). Further examples of these groups, and other protecting groups,are found in T. W. Greene, et al., Greene's Protective Groups in OrganicSynthesis. New York: Wiley Interscience, 2006.

In general, the FGFR receptors (FGFR1, FGFR2, FGFR3, and FGFR4) shareseveral structural features in common, including three extracellularimmunoglobulin-like (Ig) domains, a hydrophobic transmembrane domain,and an intracellular tyrosine kinase domain split by a kinase insertdomain, followed by a cytoplasmic c-terminal tail (Johnson et al., Adv.Cancer Res. 60:1-40,1993; and Wilkie et al., Curr. Biol.5:500-507,1995). In FGFR1, the kinase insert domain spans positions 582to 595 of the alpha A1 isoform of FGFR1 (SEQ ID NO:1). In FGFR2, thekinase insert domain spans positions 585 to 598 of the FGFR2 IIIcisoform (SEQ ID NO:3). In FGFR3, the kinase insert domain spanspositions 576 to 589 of the FGFR3 IIIc isoform (SEQ ID NO:5). In FGFR4,the kinase insert domain spans positions 571 to 584 of FGFR4 isoform 1(SEQ ID NO: 7). The c-terminal tail of FGFRs begins following the end ofthe tyrosine kinase domain and extends to the c-terminus of the protein.Several isoforms of each FGFR have been identified and are the result ofalternative splicing of their mRNAs (Johnson et al., Mol. Cell. Biol.11:4627-4634,1995; and Chellaiah et al., J. Biol. Chem.269:11620-11627,1994). Exemplary amino acid sequences for exemplarywildtype isoforms of FGFR1 are SEQ ID NO: 1 (also called the αtA1isoform of FGFR1) and SEQ ID NO: 2 (also called the αB1 isoform ofFGFR1). Exemplary amino acid sequences for exemplary wildtype isoformsof FGFR2 are SEQ ID NO: 3 (also called the IIIc isoform of FGFR2) andSEQ ID NO: 4 (also called the IIIb isoform of FGFR2). Exemplary aminoacid sequences for exemplary wildtype isoforms of FGFR3 are SEQ ID NO: 5(also called the IIIc isoform of FGFR3) and SEQ ID NO: 6 (also calledthe IIIb isoform of FGFR3). Exemplary amino acid sequences for exemplarywildtype isoforms of FGFR4 are SEQ ID NO: 7 (also called isoform 1 ofFGFR4) and SEQ ID NO: 8 (also called isoform 2 of FGFR4). These aminoacid sequences are shown in FIG. 1.

As defined herein, the “c-terminal tail” of a FGFR protein begins at anamino acid corresponding to amino acid 756 in SEQ ID NO: 1, amino acid759 in SEQ ID NO:3, 750 in SEQ ID NO: 5, or 745 in SEQ ID NO:7 and endsat the c-terminus of the protein.

A few of the receptor variants that result from this alternativesplicing have different ligand binding specificities and affinities(Zimmer et al., J. Biol. Chem. 268:7899-7903,1993; Cheon et al., Proc.Natl. Acad. Sci. U.S.A. 91:989-993,1994; and Miki et al., Proc. Natl.Acad. Sci. U.S.A. 89:246-250,1992). Protein sequences for FGFR proteinsand nucleic acids encoding FGFR proteins are known in the art.

The amino acid positions used to describe the FGFR substitutions hereinare generally specified to correspond to a particular SEQ ID NO. When aparticular SEQ ID NO is not specified, it is to be understood that theamino acid position referred to is from the first SEQ ID of thespecified FGFR (i.e., SEQ ID NO:1 for FGFR1, SEQ ID NO:3 for FGFR2, SEQID NO:5 for FGFR3, or SEQ ID NO:7 for FGFR4). A “corresponding” aminoacid position (or substitution) in a different isoform of the same FGFR(e.g., in SEQ ID NO:2, when SEQ ID NO:1 is specified) or in a differentFGFR (e.g., FGFR2 when FGFR1 is specified) can be identified byperforming a sequence alignment between the protein sequences ofinterest. In some cases, there is no corresponding amino acid positionidentified by an alignment. Some non-limiting corresponding amino acidpositions are provided in Tables BA, BD, and BE. A lack of acorresponding amino acid position in any of these Tables does notnecessarily mean that no corresponding amino acid position exists.

Signaling by FGFRs regulates key biological processes including cellproliferation, survival, migration, and differentiation. Dysregulationof a FGFR gene, a FGFR protein, or expression or activity, or level ofthe same, has been associated with many types of cancer. For example,dysregulation of FGFRs can occur by multiple mechanisms, such as FGFRgene overexpression, FGFR gene amplification, activating mutations(e.g., point mutations or truncations), and chromosomal rearrangementsthat lead to FGFR fusion proteins. Dysregulation of a FGFR gene, a FGFRprotein, or expression or activity, or level of the same, can result in(or cause in part) the development of a variety of differentFGFR-associated cancers. Non-limiting examples of the types ofFGFR-associated cancers and the dysregulation of a FGFR gene, a FGFRprotein, or expression or activity, or level of the same, that causes(or causes in part) the development of the FGFR-associated cancers arelisted in Tables BA-BD.

The term “FGFR” or “FGFR protein” includes any of the FGFR proteinsdescribed herein (e.g., a FGFR1, a FGFR2, a FGFR3 or a FGFR4 protein, orisoforms thereof).

The term “FGFR gene” includes any of the FGFR genes described herein(e.g., a FGFR1, a FGFR2, a FGFR3 gene, or a FGFR4 gene).

The ability of test compounds to act as inhibitors of FGFR1, FGFR2and/or FGFR3 may be demonstrated by the assays described in ExamplesA-E. Functional parameters (e.g., IC₅₀ values, k_(obs) values) are shownin Tables EA-EE.

Compounds of Formula I have been found to inhibit FGFR1, FGFR2 and/orFGFR3, and are therefore believed to be useful for treating diseases anddisorders which can be treated with an inhibitor of FGFR1, FGFR2, FGFR3and/or FGFR4, such as FGFR-associated diseases and disorders, e.g.,proliferative disorders such as cancers, including hematological cancersand solid tumors.

In certain embodiments, compounds of Formula I are useful for preventingdiseases and disorders as defined herein (for example cancer).

In some embodiments, compounds of Formula I are covalent inhibitors ofFGFR1, FGFR2 and/or FGFR3. Covalent inhibitors in general are known inthe medical arts (see, e.g., Singh et al, Nat. Rev. Drug. Disc.,10(4):307-317,2011; Zhao et al, Drug Discov. Today 23(3):727-735,2018).In some cases, a covalent inhibitor includes a binding moiety that canbind reversibly to a target protein and a warhead that reacts with acysteine in the target protein to form a covalent bond between theinhibitor and a cysteine residue in a target protein. The covalent bondcan be reversible or irreversible. In some cases, a warhead can beexposed through metabolic activation of an inhibitor by a subject.

Accordingly, in some aspects, this disclosure provides FGFR inhibitorsthat are compounds that can form a covalent bond with a cysteine residuein a FGFR protein. Examples of such compounds include compounds ofFormula I. In some embodiments, this disclosure provides compounds thatcan form a covalent bond with a cysteine residue in a kinase insertdomain in a FGFR protein. In some embodiments, the FGFR protein is aFGFR3 protein. In some embodiments, the cysteine residue corresponds toCys582 in SEQ ID NO: 5. For example, in some embodiments of any of themethods described herein, a compound that can form a covalent bond witha cysteine residue in a FGFR protein can be a compound that can form acovalent bond with a cysteine residue in a kinase insert domain in aFGFR protein. In some embodiments, this disclosure provides compoundsthat can form a covalent bond with a cysteine residue in a c-terminaltail of a FGFR protein. In some embodiments, the FGFR protein is a FGFR2protein. In some embodiments, the cysteine residue corresponds to Cys790in SEQ ID NO: 3. For example, in some embodiments of any of the methodsherein, a compound that can form a covalent bond with a cysteine residuein a FGFR protein can be a compound that can form a covalent bond with acysteine residue in a c-terminal tail in a FGFR protein. In someembodiments of any of the methods described herein, a compound that canform a covalent bond with a cysteine residue in a FGFR protein can be acompound that can form a covalent bond with a cysteine residue in akinase insert domain in a FGFR protein or a cysteine residue in ac-terminal tail of a FGFR protein. A covalent bond between a protein anda compound (e.g., a compound of Formula I) can be determined by anymethod known in the art. For example, washout experiments can show thatremoval of excess compound (e.g., by dialysis or gel filtration) from aprotein does not result in a recovery of activity in the protein. Asanother example, intact mass of a protein can be measured by massspectrometry and the mass of a protein and covalently bound compound canbe determined using this technique. The mass of a protein bound to acovalent compound will be greater than the mass of the protein withoutthe compound. As another example, the mass of peptides from a targetprotein can be determined using mass spectrometry, and the mass of apeptide which is covalently bound by a compound will be greater than themass of the peptide without the covalently attached compound. As anotherexample, a covalent bond can be visualized using x-ray crystallography.

Accordingly, in some aspects, this disclosure provides FGFR inhibitorsthat are compounds that form a covalent bond with a cysteine residue ina FGFR protein. Examples of such compounds include compounds of FormulaI. In some embodiments, this disclosure provides compounds that form acovalent bond with a cysteine residue in a kinase insert domain in aFGFR protein. In some embodiments, the FGFR protein is a FGFR3 protein.In some embodiments, the cysteine residue corresponds to Cys582 in SEQID NO: 5. For example, in some embodiments of any of the methodsdescribed herein, a compound that forms a covalent bond with a cysteineresidue in a FGFR protein can be a compound that forms a covalent bondwith a cysteine residue in a kinase insert domain in a FGFR protein. Insome embodiments, this disclosure provides compounds that form acovalent bond with a cysteine residue in a c-terminal tail of a FGFRprotein. In some embodiments, the FGFR protein is a FGFR2 protein. Insome embodiments, the cysteine residue corresponds to Cys790 in SEQ IDNO: 3. For example, in some embodiments of any of the methods herein, acompound that forms a covalent bond with a cysteine residue in a FGFRprotein can be a compound that forms a covalent bond with a cysteineresidue in a c-terminal tail in a FGFR protein. In some embodiments ofany of the methods described herein, a compound that forms a covalentbond with a cysteine residue in a FGFR protein can be a compound thatforms a covalent bond with a cysteine residue in a kinase insert domainin a FGFR protein or a cysteine residue in a c-terminal tail of a FGFRprotein.

In one aspect, this disclosure provides FGFR3 inhibitors of Formula Ithat are at least about 3-fold (e.g., at least about 4-, 5-, 6-, 7-, 8-,9-, 10-, 15-, 20-, 30-, 40-, 50-, 75-, 100-, 200-, 500-, 1000-fold, ormore) more selective for FGFR3 than for FGFR1. In some embodiments, suchan inhibitor can form a covalent bond with a cysteine in a kinase insertdomain in a FGFR3 protein. In some embodiments, such an inhibitor formsa covalent bond with a cysteine in a kinase insert domain in a FGFR3protein. In some embodiments, the cysteine corresponds to Cys582 of SEQID NO: 5.

In one aspect, this disclosure provides FGFR2 inhibitors of Formula Ithat are at least about 3-fold (e.g., at least about 4-, 5-, 6-, 7-, 8-,9-, 10-, 15-, 20-, 30-, 40-, 50-, 75-, 100-, 200-, 500-, 1000-fold, ormore) more selective for FGFR2 than for FGFR1. In some embodiments, suchan inhibitor can form a covalent bond with a cysteine in a c-terminaltail in a FGFR2 protein. In some embodiments, such an inhibitor forms acovalent bond with a cysteine in a c-terminal tail in a FGFR2 protein.In some embodiments, the cysteine corresponds to Cys790 of SEQ ID NO: 3.

In another aspect, this disclosure provides an inhibited FGFR3 proteincovalently bound to a molecule via a cysteine in the kinase insertdomain of the FGFR3 protein. In some embodiments, the cysteinecorresponds to Cys582 of SEQ ID NO: 5. In some embodiments, the moleculeis a compound of Formula I. In some embodiments, the molecule is atleast about 3-fold (e.g., 4-, 5-, at least about 6-, 7-, 8-, 9-, 10-,15-, 20-, 30-, 40-, 50-, 75-, 100-, 200-, 500-, 1000-fold, or more) moreselective for FGFR3 than for FGFR1.

In another aspect, this disclosure provides an inhibited FGFR2 proteincovalently bound to a molecule via a cysteine in the c-terminal tail ofthe FGFR2 protein. In some embodiments, the cysteine corresponds toCys790 of SEQ ID NO: 3. In some embodiments, the molecule is a compoundof Formula I. In some embodiments, the molecule is at least about 3-fold(e.g., at least about 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 30-, 40-,50-, 75-, 100-, 200-, 500-, 1000-fold, or more) more selective for FGFR2than for FGFR1.

In another aspect, this disclosure also provides a compound of Formula Icovalently bonded to a cysteine. In some embodiments, the cysteine is ina kinase insert domain of a protein. In some embodiments, the cysteineis in a c-terminal tail of a protein. In some embodiments, the proteinis a FGFR protein. In some embodiments, the protein is a FGFR3 protein.In some embodiments, the cysteine corresponds to Cys582 of SEQ ID NO: 5.In some embodiments, the cysteine is in a kinase insert domain of aFGFR3 protein. In some embodiments, the compound is at least about3-fold (e.g., at least about 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 30-,40-, 50-, 75-, 100-, 200-, 500-, 1000-fold, or more) more selective forFGFR3 than for FGFR1. In some embodiments, the protein is a FGFR2protein. In some embodiments, the cysteine is in a c-terminal tail of aFGFR2 protein. In some embodiments, the cysteine corresponds to Cys790of SEQ ID NO: 3. In some embodiments, the compound is at least about3-fold (e.g., at least about 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 30-,40-, 50-, 75-, 100-, 200-, 500-, 1000-fold, or more) more selective forFGFR2 than for FGFR1.

In another aspect, this disclosure provides an inhibited kinase proteincovalently bonded to a compound of Formula I. In some embodiments, theinhibited kinase protein is covalently bonded to a compound of Formula Ivia a cysteine in the kinase protein. In some embodiments, the kinaseprotein is a tyrosine kinase. In some embodiments, the kinase protein isa FGFR protein. In some embodiments, the kinase protein is a FGFR3protein. In some embodiments, the cysteine is a cysteine in a kinaseinsert domain of a FGFR3 protein. In some embodiments, the cysteinecorresponds to Cys582 of SEQ ID NO: 5. In some embodiments, the kinaseprotein is a FGFR2 protein. In some embodiments, the cysteine is acysteine in a c-terminal tail of a FGFR2 protein. In some embodiments,the cysteine corresponds to Cys790 of SEQ ID NO: 3.

In another aspect, this disclosure provides a compound of Formula I,wherein the compound forms a covalent bond with a cysteine in a FGFRprotein. This disclosure also provides a compound of Formula I, whereinthe compound can form a covalent bond with a cysteine in a FGFR protein.In some embodiments, the cysteine is a cysteine in a kinase insertdomain of a FGFR protein or a cysteine in a c-terminal tail of a FGFRprotein. In some embodiments, the compound is at least about 3-fold(e.g., at least about 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 30-, 40-,50-, 75-, 100-, 200-, 500-, 1000-fold, or more) more selective for FGFR3than for FGFR1. In some embodiments, the cysteine corresponds to Cys582of SEQ ID NO: 5. In some embodiments, the compound is at least about3-fold (e.g., at least about 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 30-,40-, 50-, 75-, 100-, 200-, 500-, 1000-fold, or more) more selective forFGFR2 than for FGFR1. In some embodiments, the cysteine corresponds toCys790 of SEQ ID NO: 3.

In another aspect, this disclosure provides a compound of Formula I,wherein the compound forms a covalent bond with a cysteine in a kinaseinsert domain in a FGFR3 protein. This disclosure also provides acompound of Formula I, wherein the compound can form a covalent bondwith a cysteine in a kinase insert domain in a FGFR3 protein. In someembodiments, the compound is at least about 3-fold (e.g., at least about4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 30-, 40-, 50-, 75-, 100-, 200-,500-, 1000-fold, or more) more selective for FGFR3 than for FGFR1. Insome embodiments, the cysteine corresponds to Cys582 of SEQ ID NO: 5.

In another aspect, this disclosure provides a compound of Formula I,wherein the compound forms a covalent bond with a cysteine in ac-terminal tail in a FGFR2 protein. This disclosure also provides acompound of Formula I, wherein the compound can form a covalent bondwith a cysteine in a c-terminal tail in a FGFR2 protein. In someembodiments, the compound is at least about 3-fold (e.g., at least about4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 30-, 40-, 50-, 75-, 100-, 200-,500-, 1000-fold, or more) more selective for FGFR2 than for FGFR1. Insome embodiments, the cysteine corresponds to Cys790 of SEQ ID NO: 3.

In certain embodiments, compounds that can form a covalent bond with acysteine residue in a FGFR protein are useful for preventing diseases ordisorders as defined herein (for example cancer). In certainembodiments, compounds that form a covalent bond with a cysteine residuein a FGFR protein are useful for preventing diseases or disorders asdefined herein (for example cancer).

As used herein, “an inhibited FGFR protein covalently bound to amolecule via a cysteine” means that the molecule has an IC₅₀ value ofless than about 500 nM, as determined by any of the assays described inExamples A, B, D, or E.

In some embodiments, the compounds provided herein (e.g., compounds ofFormula I) exhibit potent and selective FGFR inhibition. For example,the compounds provided herein can exhibit nanomolar potency against wildtype FGFR and a FGFR kinase encoded by a FGFR gene including anactivating mutation or a FGFR kinase inhibitor resistance mutation,including, for example, the FGFR3-TACC3 fusion, and gatekeeper mutations(corresponding to V561M in SEQ ID NO:1, V564F or V564I in SEQ ID NO:3,V555M in SEQ ID NO:5, or V550L, V550M, or V550E in SEQ ID NO:7), withminimal activity against related kinases.

In some embodiments, the compounds provided herein (e.g., compounds ofFormula I) exhibit nanomolar potency against an altered FGFR fusionprotein encoded by a FGFR gene encoding the FGFR fusion protein (e.g.any of the FGFR fusion proteins described herein including, withoutlimitation, FGFR3-TACC3 or FGFR2-BICC1) which FGFR gene includes a FGFRkinase inhibitor resistance mutation (e.g., any of the FGFR mutationsdescribed herein including, without limitation, mutations correspondingto V561M in SEQ ID NO:1, V564F in SEQ ID NO:3, V555M in SEQ ID NO:5, orV550L, V550M, or V550E in SEQ ID NO:7) such that the altered FGFRprotein is a FGFR fusion protein that exhibits FGFR kinase resistancedue to the presence of a FGFR kinase inhibitor resistance amino acidsubstitution or deletion. Non-limiting examples includeFGFR3-TACC3-V555M and FGFR2-BICC1-V564F. In some embodiments, thecompounds provided herein exhibit nanomolar potency against an alteredFGFR protein encoded by a FGFR gene that that includes a FGFR mutation(e.g. any of the FGFR mutations described herein including, withoutlimitation, FGFR2 N549K or FGFR3 N540K) and that includes a FGFR kinaseinhibitor resistance mutation (e.g., any of the FGFR kinase inhibitorresistance mutations described herein including, without limitation,FGFR1 N546K, FGFR2 K659E, or FGFR3 V555M) such that the altered FGFRprotein includes a FGFR substitution caused by the FGFR mutation (e.g.,a FGFR primary mutation) and the altered FGFR protein exhibits FGFRkinase resistance due to the presence of a FGFR kinase inhibitorresistance amino acid substitution or deletion.

In some embodiments, the compounds of Formula I or a pharmaceuticallyacceptable salt or solvate thereof, selectively target a FGFR kinase.For example, a compound of Formula I or a pharmaceutically acceptablesalt or solvate thereof, can selectively target a FGFR kinase overanother kinase or non-kinase target.

As used herein, the “selectivity” of a compound for a first target overa second target means that the compound has more potent activity at thefirst target than the second target. A fold selectivity can becalculated by any method known in the art. For example, a foldselectivity can be calculated by dividing the IC₅₀ value of a compoundfor the second target (e.g., FGFR1) by the IC₅₀ value of the samecompound for the first target (e.g., FGFR2 or FGFR3). An IC₅₀ value canbe determined by any method known in the art. For example, an IC₅₀ valuecan be determined by any of the methods described in Examples A, B, D,or E. As another example, a fold selectivity can be calculated bydividing the observed rate of covalent modification (e.g., a k_(obs)value) for the first target (e.g., FGFR2 or FGFR3) by the k_(obs) valuefor the second target (e.g., FGFR1). A k_(obs) value can be determinedby any method known in the art. For example, a k_(obs) value can bedetermined by the method described in Example C. In some embodiments, acompound is first determined to have an activity of less than 500 nM forthe first target. In some embodiments, a compound is first determined tohave an activity of less than 500 nM for the second target.

As another example, a k_(obs) value can be determined as follows. A LCMSassay is used to determine of the extent of covalent modification of theintact FGFR1 or FGFR3 protein over time. The proteins are first dilutedto 2× concentration in partial assay buffer [25.0 mM HEPES(4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) pH 7.5, 150.0 mMNaCl, 5.0 mM MgCl₂, 0.5 mM tris(2-carboxyethyl) phosphine (TCEP), and10.0 mM octyl β-D-glucopyranoside (β-OG)]. Compound dilutions areperformed in 3 steps. All are initially diluted in dimethyl sulfoxide(DMSO) to a concentration equal to 25× the final assay concentration.The initial stocks are then diluted 12.5× in partial assay buffer suchthat the final concentration is 2× the assay concentration and 8% (v:v)DMSO. The assay is initiated by a final dilution of 10 μL of 2× compoundinto 10 μL of 2× protein. Final assay buffer conditions are 25.0 mMHEPES pH 7.5, 150.0 mM NaCl, 5.0 mM MgCl₂, 0.5 mM TCEP, and 10.0 mMβ-OG,0 4% DMSO. Final protein and compound concentrations are 0.5 μMprotein and either 0.0 or 3.0 μM compound. The 0.0 μM compound (DMSOControl) samples are used as a tool to assess the protein stabilityduring the assay, and to normalize the mass spec signals across samplesduring the data processing stage. Protein and compound reactions areallowed to proceed for varying lengths of time and upon reaching anappropriate incubation, the reactions are quenched by the addition of 20μL of 0.4% formic acid. Quenched reactions are then analyzed on eitheran Agilent 6520A or Agilent 6545XT ESI-QTOF mass spectrometer inpositive ion mode.

The reactions are injected onto an Agilent Poroshell C3 column running asolvent system of 0.1% formic acid: acetonitrile+0.1% formic acid(85:15%). A gradient is developed by running 15% to 95%acetonitrile+0.1% formic acid over 1 minute. Mass spec data arecollected throughout the entire gradient. Protein signals are thenautomatically deconvolved using Agilent Masshunter software. Deconvolvedmass signals are exported to Tibco Spotfire data analysis program forfurther processing and normalization.

Data analysis includes five steps. First, the signals for the “DMSOControls” are analyzed to determine the percent of signal associatedwith unmodified FGFR1 or FGFR3 at each timepoint. Next, the percent ofthe signal associated with the covalent modification is determined.Third, the average nonmodified “DMSO Control” signal is used tonormalize the modified protein signals at each timepoint. Thisnormalized value is coined “Normalized Percent of Control” or POC. A POCvalue that increases over time is consistent with a protein showingincreasing modification over time.

${POC} = {\frac{\%_{Modified}}{\%_{{Unmodified}\mspace{14mu}{Control}}} \times 100}$

The POC values are refit to a standard exponential growth modelresulting in an observed rate (k_(obs)) of modification of the protein.

POC=[% Modified]₀ ×e ^(−k) ^(obs,) ^(t)

Where:

-   -   POC=Normalized POC value    -   [% Modified]₀=Initial amount of modified protein (%)    -   k_(obs.)=Observed rate (min⁻¹)    -   t=time (min)

In some embodiments, a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof exhibits at least a 30-foldselectivity for a FGFR kinase over another kinase. For example, acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof, exhibits at least a 40-fold selectivity; at least a 50-foldselectivity; at least a 60-fold selectivity; at least a 70-foldselectivity; at least a 80-fold selectivity; at least a 90-foldselectivity; at least 100-fold selectivity; at least 200-foldselectivity; at least 300-fold selectivity; at least 400-foldselectivity; at least 500-fold selectivity; at least 600-foldselectivity; at least 700-fold selectivity; at least 800-foldselectivity; at least 900-fold selectivity; or at least 1000-foldselectivity for a FGFR kinase over another kinase. In some embodiments,selectivity for a FGFR kinase over another kinase is measured in acellular assay (e.g., a cellular assay as provided herein).

In some embodiments, the compounds provided herein (e.g., compounds ofFormula I) can exhibit selectivity for a FGFR kinase over a KDR kinase(e.g., VEGFR2). In some embodiments, the selectivity for a FGFR kinaseover a KDR kinase is observed without loss of potency for a FGFR kinaseencoded by a FGFR gene including an activating mutation or a FGFR kinaseinhibitor resistance mutation (e.g., a gatekeeper mutant). In someembodiments, the selectivity over a KDR kinase is at least 10-fold(e.g., at least a 40-fold selectivity; at least a 50-fold selectivity;at least a 60-fold selectivity; at least a 70-fold selectivity; at leasta 80-fold selectivity; at least a 90-fold selectivity; at least 100-foldselectivity; at least 150-fold selectivity; at least 200-foldselectivity; at least 250-fold selectivity; at least 300-foldselectivity; at least 350-fold selectivity; or at least 400-foldselectivity) as compared to the inhibition of FGFR3-TACC3 (e.g., thecompounds are more potent against FGFR3-TACC3 than KDR). In someembodiments, the selectivity for a FGFR kinase over a KDR kinase isabout 30-fold. In some embodiments, the selectivity for a FGFR kinaseover a KDR kinase is at least 100-fold. In some embodiments, theselectivity for a FGFR kinase over a KDR kinase is at least 150-fold. Insome embodiments, the selectivity for a FGFR kinase over a KDR kinase isat least 400-fold. Without being bound by any theory, potent KDR kinaseinhibition is believed to be a common feature among multikinaseinhibitors (MKIs) that target FGFR and may be the source of thedose-limiting toxicities observed with such compounds.

In some embodiments, the compounds provided herein (e.g., compounds ofFormula I) can exhibit selectivity for a FGFR kinase over an Aurora Bkinase (e.g., VEGFR2). In some embodiments, the selectivity for a FGFRkinase over an Aurora B kinase is observed without loss of potency for aFGFR kinase encoded by a FGFR gene including an activating mutation or aFGFR kinase inhibitor resistance mutation (e.g., a gatekeeper mutant).In some embodiments, the selectivity over an Aurora B kinase is at least10-fold (e.g., at least a 40-fold selectivity; at least a 50-foldselectivity; at least a 60-fold selectivity; at least a 70-foldselectivity; at least a 80-fold selectivity; at least a 90-foldselectivity; at least 100-fold selectivity; at least 150-foldselectivity; at least 200-fold selectivity; at least 250-foldselectivity; at least 300-fold selectivity; at least 350-foldselectivity; or at least 400-fold selectivity) as compared to theinhibition of FGFR3-TACC3 (e.g., the compounds are more potent againstFGFR3-TACC3 than KDR). In some embodiments, the selectivity for a FGFRkinase over an Aurora B kinase is about 30-fold. In some embodiments,the selectivity for a FGFR kinase over an Aurora B kinase is at least100-fold. In some embodiments, the selectivity for a FGFR kinase over anAurora B kinase is at least 150-fold. In some embodiments, theselectivity for a FGFR kinase over an Aurora B kinase is at least400-fold. Without being bound by any theory, potent KDR kinaseinhibition is believed to be a common feature among multikinaseinhibitors (MKIs) that target FGFR and may be the source of thedose-limiting toxicities observed with such compounds.

In some embodiments, the compounds provided herein (e.g., compounds ofFormula I) can exhibit selectivity for a first FGFR family member (e.g.,FGFR2 or FGFR3) over a second FGFR family member (e.g., FGFR1 or FGFR4).In some embodiments, the selectivity for a first FGFR family member overa second FGFR family member is observed without loss of potency for thefirst FGFR family member, or activating or resistance mutations thereof.In some embodiments, the selectivity over a second FGFR family member isat least 10-fold (e.g., at least a 40-fold selectivity; at least a50-fold selectivity; at least a 60-fold selectivity; at least a 70-foldselectivity; at least a 80-fold selectivity; at least a 90-foldselectivity; at least 100-fold selectivity; at least 150-foldselectivity; at least 200-fold selectivity; at least 250-foldselectivity; at least 300-fold selectivity; at least 350-foldselectivity; or at least 400-fold selectivity) as compared to theinhibition of the first FGFR family member (e.g., the compounds are morepotent against FGFR3 than FGFR1). In some embodiments, the selectivityfor a first FGFR family member over a second FGFR family member is about30-fold. In some embodiments, the selectivity for a first FGFR familymember over a second FGFR family member is at least 100-fold. In someembodiments, the selectivity for a first FGFR family member over asecond FGFR family member is at least 150-fold. In some embodiments, theselectivity for a first FGFR family member over a second FGFR familymember is at least 400-fold. Without being bound by any theory, it isbelieved that selectivity over FGFR1 can reduce side effects associatedwith its inhibition (e.g., elevated phosphate level (e.g.,hyperphosphatemia)).

In some embodiments, inhibition of FGFR1V561M is similar to thatobserved for wild-type FGFR1. For example, inhibition of V561M is withinabout 2-fold (e.g., about 5-fold, about 7-fold, about 10-fold) ofinhibition of wild-type FGFR1 (e.g., the compounds are similarly potentagainst wild-type FGFR1 and V561M). In some embodiments, selectivity fora wildtype or V561M FGFR1 kinase over another kinase is measured in anenzyme assay (e.g., an enzyme assay as provided herein). In someembodiments, the compounds provided herein (e.g., compounds of FormulaI) exhibit selective cytotoxicity to FGFR1-mutant cells.

In some embodiments, inhibition of FGFR2 V564I or V564F is similar tothat observed for wild-type FGFR2. For example, inhibition of V565I orV565F is within about 2-fold (e.g., about 5-fold, about 7-fold, about10-fold) of inhibition of wild-type FGFR2 (e.g., the compounds aresimilarly potent against wild-type FGFR2 and V565I or V565F). In someembodiments, selectivity for a wildtype or V565I or V565F FGFR2 kinaseover another kinase is measured in an enzyme assay (e.g., an enzymeassay as provided herein). In some embodiments, the compounds providedherein (e.g., compounds of Formula I) exhibit selective cytotoxicity toFGFR2-mutant cells.

In some embodiments, inhibition of FGFR3 V555M is similar to thatobserved for wild-type FGFR3. For example, inhibition of V555M is withinabout 2-fold (e.g., about 5-fold, about 7-fold, about 10-fold) ofinhibition of wild-type FGFR3 (e.g., the compounds are similarly potentagainst wild-type FGFR3 and V555M). In some embodiments, selectivity fora wildtype or V555M FGFR 3kinase over another kinase is measured in anenzyme assay (e.g., an enzyme assay as provided herein). In someembodiments, the compounds provided herein (e.g., compounds of FormulaI) exhibit selective cytotoxicity to FGFR3-mutant cells.

In some embodiments, the compounds provided herein (e.g., compounds ofFormula I) exhibit brain and/or central nervous system (CNS) penetrance.Such compounds are capable of crossing the blood brain barrier andinhibiting a FGFR kinase in the brain and/or other CNS structures. Insome embodiments, the compounds provided herein are capable of crossingthe blood brain barrier in a therapeutically effective amount. Forexample, treatment of a subject with cancer (e.g., a FGFR-associatedcancer such as a FGFR-associated brain or CNS cancer) can includeadministration (e.g., oral administration) of the compound to thesubject. In some such embodiments, the compounds provided herein areuseful for treating a primary brain tumor or metastatic brain tumor. Forexample, a FGFR-associated primary brain tumor or metastatic braintumor.

In some embodiments, the compounds of Formula I or a pharmaceuticallyacceptable salt or solvate thereof, exhibit one or more of high GIabsorption, low clearance, and low potential for drug-drug interactions.

Compounds of Formula I are useful for treating diseases and disorderswhich can be treated with a FGFR kinase inhibitor, such asFGFR-associated diseases and disorders, e.g., proliferative disorderssuch as cancers, including hematological cancers and solid tumors,angiogenesis-related disorders, and developmental disorders such asachondroplasia, hypochondroplasia, or thanatophoric dysplasia.

The term “preventing” as used herein means the prevention of therecurrence or spread, in whole or in part, of the disease or conditionas described herein, or a symptom thereof.

As used herein, the word “a” before a noun represents one or more of theparticular noun. For example, the phrase “a cell” represents “one ormore cells.”

As used herein, terms “treat” or “treatment” refer to therapeutic orpalliative measures. Beneficial or desired clinical results include, butare not limited to, alleviation, in whole or in part, of symptomsassociated with a disease or disorder or condition, diminishment of theextent of disease, stabilized (i.e., not worsening) state of disease,delay or slowing of disease progression, amelioration or palliation ofthe disease state (e.g., one or more symptoms of the disease), andremission (whether partial or total), whether detectable orundetectable. “Treatment” can also mean prolonging survival as comparedto expected survival if not receiving treatment.

As used herein, the terms “subject,” “individual,” or “patient,” areused interchangeably, refers to any animal, including mammals such asmice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, primates, and humans. In some embodiments, the patient is ahuman. In some embodiments, the subject has experienced and/or exhibitedat least one symptom of the disease or disorder to be treated and/orprevented. In some embodiments, the subject has been identified ordiagnosed as having a cancer with a dysregulation of a FGFR gene, a FGFRprotein, or expression or activity, or level of any of the same (aFGFR-associated cancer) (e.g., as determined using a regulatoryagency-approved, e.g., FDA-approved, assay or kit). In some embodiments,the subject has a tumor that is positive for a dysregulation of a FGFRgene, a FGFR protein, or expression or activity, or level of any of thesame (e.g., as determined using a regulatory agency-approved assay orkit). The subject can be a subject with a tumor(s) that is positive fora dysregulation of a FGFR gene, a FGFR protein, or expression oractivity, or level of any of the same (e.g., identified as positiveusing a regulatory agency-approved, e.g., FDA-approved, assay or kit).The subject can be a subject whose tumors have a dysregulation of a FGFRgene, a FGFR protein, or expression or activity, or a level of the same(e.g., where the tumor is identified as such using a regulatoryagency-approved, e.g., FDA-approved, kit or assay). In some embodiments,the subject is suspected of having a FGFR-associated cancer. In someembodiments, the subject has a clinical record indicating that thesubject has a tumor that has a dysregulation of a FGFR gene, a FGFRprotein, or expression or activity, or level of any of the same (andoptionally the clinical record indicates that the subject should betreated with any of the compositions provided herein). In someembodiments, the patient is a pediatric patient. In some embodiments,the patient is in utero.

The term “pediatric patient” as used herein refers to a patient underthe age of 21 years at the time of diagnosis or treatment. The term“pediatric” can be further be divided into various subpopulationsincluding: neonates (from birth through the first month of life);infants (1 month up to two years of age); children (two years of age upto 12 years of age); and adolescents (12 years of age through 21 yearsof age (up to, but not including, the twenty-second birthday)). BerhmanR E, Kliegman R, Arvin A M, Nelson W E. Nelson Textbook of Pediatrics,15th Ed. Philadelphia: W. B. Saunders Company, 1996; Rudolph A M, et al.Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and AveryMD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins;1994. In some embodiments, a pediatric patient is from birth through thefirst 28 days of life, from 29 days of age to less than two years ofage, from two years of age to less than 12 years of age, or 12 years ofage through 21 years of age (up to, but not including, the twenty-secondbirthday). In some embodiments, a pediatric patient is from birththrough the first 28 days of life, from 29 days of age to less than 1year of age, from one month of age to less than four months of age, fromthree months of age to less than seven months of age, from six months ofage to less than 1 year of age, from 1 year of age to less than 2 yearsof age, from 2 years of age to less than 3 years of age, from 2 years ofage to less than seven years of age, from 3 years of age to less than 5years of age, from 5 years of age to less than 10 years of age, from 6years of age to less than 13 years of age, from 10 years of age to lessthan 15 years of age, or from 15 years of age to less than 22 years ofage.

In certain embodiments, compounds disclosed herein (e.g., compounds ofFormula I) are useful for preventing diseases and disorders as definedherein (for example, autoimmune diseases, inflammatory diseases, andcancer). The term “preventing” as used herein means the prevention ofthe onset, recurrence or spread, in whole or in part, of the disease orcondition as described herein, or a symptom thereof.

The term “FGFR-associated disease or disorder” as used herein refers todiseases or disorders associated with or having a dysregulation of aFGFR gene, a FGFR kinase (also called herein FGFR kinase protein or FGFRprotein), or the expression or activity or level of any (e.g., one ormore) of the same (e.g., any of the types of dysregulation of a FGFRgene, a FGFR kinase, a FGFR kinase domain, or the expression or activityor level of any of the same described herein). Non-limiting examples ofa FGFR-associated disease or disorder include, for example, cancer,angiogenesis-related disorders, and developmental disorders such asachondroplasia, hypochondroplasia, or thanatophoric dysplasia. In someembodiments of any of the methods described herein, a FGFR-associateddisease or disorder can be a FGFR1-associated disorder. In someembodiments of any of the methods described herein, a FGFR-associateddisease or disorder can be a FGFR2-associated disease or disorder. Insome embodiments of any of the methods described herein, aFGFR-associated disease or disorder can be a FGFR3-associated disease ordisorder. In some embodiments of any of the methods described herein, aFGFR-associated disease or disorder can be a FGFR4-associated disease ordisorder.

The term “FGFR-associated cancer” as used herein refers to cancersassociated with or having a dysregulation of a FGFR gene, a FGFR kinase(also called herein FGFR kinase protein), or expression or activity, orlevel of any of the same. Non-limiting examples of a FGFR-associatedcancer are described herein. In some embodiments of any of the methodsdescribed herein, a FGFR-associated cancer can be a FGFR1-associatedcancer. In some embodiments of any of the methods described herein, aFGFR-associated cancer can be a FGFR2-associated cancer. In someembodiments of any of the methods described herein, a FGFR-associatedcancer can be a FGFR3-associated cancer. In some embodiments of any ofthe methods described herein, a FGFR-associated cancer can be aFGFR4-associated cancer.

The phrase “dysregulation of a FGFR gene, a FGFR kinase, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a chromosomal translocation that results in theexpression of a fusion protein including a FGFR kinase domain and afusion partner, a mutation in a FGFR gene that results in the expressionof a FGFR protein that includes a deletion of at least one amino acid ascompared to a wildtype FGFR protein, a mutation in a FGFR gene thatresults in the expression of a FGFR protein with one or more pointmutations as compared to a wildtype FGFR protein, a mutation in a FGFRgene that results in the expression of a FGFR protein with at least oneinserted amino acid as compared to a wildtype FGFR protein, a geneduplication that results in an increased level of FGFR protein in acell, or a mutation in a regulatory sequence (e.g., a promoter and/orenhancer) that results in an increased level of FGFR protein in a cell),an alternative spliced version of a FGFR mRNA that results in a FGFRprotein having a deletion of at least one amino acid in the FGFR proteinas compared to the wild-type FGFR protein), or increased expression(e.g., increased levels) of a wildtype FGFR kinase in a mammalian celldue to aberrant cell signaling and/or dysregulated autocrine/paracrinesignaling (e.g., as compared to a control non-cancerous cell). Asanother example, a dysregulation of a FGFR gene, a FGFR protein, orexpression or activity, or level of any of the same, can be a mutationin a FGFR gene that encodes a FGFR protein that is constitutively activeor has increased activity as compared to a protein encoded by a FGFRgene that does not include the mutation. For example, a dysregulation ofa FGFR gene, a FGFR protein, or expression or activity, or level of anyof the same, can be the result of a gene or chromosome translocationwhich results in the expression of a fusion protein that contains afirst portion of FGFR that includes a functional kinase domain, and asecond portion of a partner protein (i.e., that is not FGFR). In someexamples, dysregulation of a FGFR gene, a FGFR protein, or expression oractivity or level of any of the same can be a result of a genetranslocation of one FGFR gene with another non-FGFR gene. Non-limitingexamples of fusion proteins are described in Table BA. Non-limitingexamples of FGFR kinase protein point mutations/insertions/deletions aredescribed in Table BC. Additional examples of FGFR kinase proteinmutations (e.g., point mutations) are FGFR inhibitor resistancemutations. Non-limiting examples of FGFR inhibitor resistance mutationsare described in Table BE.

In some embodiments, dysregulation of a FGFR gene, a FGFR kinase, or theexpression or activity or level of any of the same can be caused by anactivating mutation in a FGFR gene (see, e.g., chromosome translocationsthat result in the expression of any of the fusion proteins listed inTable BA). In some embodiments, dysregulation of a FGFR gene, a FGFRkinase, or the expression or activity or level of any of the same can becaused by a genetic mutation that results in the expression of a FGFRkinase that has increased resistance to inhibition by a FGFR kinaseinhibitor and/or a multi-kinase inhibitor (MKI), e.g., as compared to awildtype FGFR kinase (see, e.g., the amino acid substitutions in TableBC). In some embodiments, dysregulation of a FGFR gene, a FGFR kinase,or the expression or activity or level of any of the same can be causedby a mutation in a nucleic acid encoding an altered FGFR protein (e.g.,a FGFR fusion protein or a FGFR protein having a mutation (e.g., aprimary mutation)) that results in the expression of an altered FGFRprotein that has increased resistance to inhibition by a FGFR kinaseinhibitor and/or a multi-kinase inhibitor (MKI), e.g., as compared to awildtype FGFR kinase (see, e.g., the amino acid substitutions in TableBC). The exemplary FGFR kinase point mutations, insertions, anddeletions shown in Table BC can be caused by an activating mutationand/or can result in the expression of a FGFR kinase that has increasedresistance to inhibition by a FGFR kinase inhibitor and/or amulti-kinase inhibitor (MKI).

For example, deregulation of a FGFR1 gene, a FGFR1 protein, orexpression or activity, or level of the same, can include FGFR1 geneamplification, a FGFR1 gene fusion from those listed in Table BA, and/orone or more point mutations selected from those listed in Table BC(e.g., one of more of T141R, R445W, N546K, V561M, K656E, and G818R).Dysregulation of a FGFR2 gene, a FGFR2 protein, or expression oractivity, or level of the same, can, e.g., include FGFR2 geneamplification, a FGFR2 gene fusion from those listed in Table BA, and/orone or more point mutations selected from those listed in Table BC(e.g., one or more of S252W, P253R, A315T, D336N, Y375C, C382R, V395D,D471N, 1547V, N549K, N549Y, V565I, V565F, and K659E). Dysregulation of aFGFR3 gene, a FGFR3 protein, or expression or activity, or level of thesame can, e.g., include FGFR3 gene amplification, a FGFR3 gene fusionfrom those listed in Table BA, and/or one or more point mutationsselected from those listed in Table BC (e.g., one or more of S131L,R248C, S249C, G370C, S371C, Y373C, G380R, R399C, E627K, K650E, K650M,V555M, V554L, V677I, and D785Y). Dysregulation of a FGFR4 gene, a FGFR4protein, or expression or activity, or level of the same can, e.g.,include FGFR4 gene amplification and/or one or more point mutationsselected from those listed in Table BC (e.g., one or more of R183S,R434Q, D425N in FGFR4 isoform 2, V550L, and R610H).

Additional examples of FGFR fusion proteins, FGFR point mutations, FGFRgene overexpression, or FGFR gene amplification that cause (or cause inpart) the development of a FGFR-associated cancer are described in: Wuet al., Cancer Discovery 3:636, 2013; Wesche et al., Biochem. J.437:199-213,2011; Gallo et al., Cytokine Growth Factor Rev.26:425-449,2015; Parker et al., J. Pathol. 232:4-15,2014; Katoh et al.,Expert Rev. Anticancer Res. 10:1375-1379,2010; Chang et al., PLoS One9:e105524,2014; Kelleher et al., Carcinogenesis 34:2198-2205,2013; Katohet al., Med. Res. Rev. 34:280-300,2014; Knights et al., Pharmacol.Therapeutics 125:105-117,2010; Turner et al., Sci. Transl. Med.2:62ps56,2010; Dutt et al., PLoS One 6(6):e20351,2011; Weiss et al.,Sci. Transl. Med. 2:62ra93,2010; Becker et al., J. Neurophatol. Exp.Neurol. 74:743-754,2015; Byron et al., PLoS One 7(2):e30801,2012; vanRhihn et al., Eur. J. Human Genetics 10:819-824,2002; Hart et al.,Oncogene 19(29)3309-3320,2000; Lin et al., Cancer Res. 68:664-673,2008;and Helsten et al., Clin. Cancer Res., e-publication dated Sep. 15, 2015(each of which is incorporated herein by reference). Additionalnon-limiting aspects and examples of FGFR fusion proteins, FGFR pointmutations, FGFR gene overexpression, or FGFR gene amplification aredescribed below.

The term “activating mutation” describes a mutation in a FGFR kinasegene that results in the expression of a FGFR kinase that has anincreased kinase activity, e.g., as compared to a wildtype FGFR kinase,e.g., when assayed under identical conditions. For example, anactivating mutation can result in the expression of a fusion proteinthat includes a FGFR kinase domain and a fusion partner. In anotherexample, an activating mutation can be a mutation in a FGFR kinase genethat results in the expression of a FGFR kinase that has one or more(e.g., two, three, four, five, six, seven, eight, nine, or ten) aminoacid substitutions (e.g., any combination of any of the amino acidsubstitutions described herein) that has increased kinase activity,e.g., as compared to a wildtype FGFR kinase, e.g., when assayed underidentical conditions. In another example, an activating mutation can bea mutation in a FGFR kinase gene that results in the expression of aFGFR kinase that has one or more (e.g., two, three, four, five, six,seven, eight, nine, or ten) amino acids deleted, e.g., as compared to awildtype FGFR kinase, e.g., when assayed under identical conditions. Inanother example, an activating mutation can be a mutation in a FGFRkinase gene that results in the expression of a FGFR kinase that has atleast one (e.g., at least 2, at least 3, at least 4, at least 5, atleast 6, at least 7, at least 8, at least 9, at least 10, at least 12,at least 14, at least 16, at least 18, or at least 20) amino acidinserted as compared to a wildtype FGFR kinase, e.g., the exemplarywildtype FGFR kinase described herein, e.g., when assayed underidentical conditions. Additional examples of activating mutations areknown in the art.

The term “wildtype” or “wild-type” describes a nucleic acid (e.g., aFGFR gene or a FGFR mRNA) or protein (e.g., a FGFR protein) that isfound in a subject that does not have a FGFR-associated disease, e.g., aFGFR-associated cancer (and optionally also does not have an increasedrisk of developing a FGFR-associated disease and/or is not suspected ofhaving a FGFR-associated disease), or is found in a cell or tissue froma subject that does not have a FGFR-associated disease, e.g., aFGFR-associated cancer (and optionally also does not have an increasedrisk of developing a FGFR-associated disease and/or is not suspected ofhaving a FGFR-associated disease).

The term “regulatory agency” refers to a country's agency for theapproval of the medical use of pharmaceutical agents with the country.For example, a non-limiting example of a regulatory agency is the U.S.Food and Drug Administration (FDA).

Provided herein is a method of treating cancer (e.g., a FGFR-associatedcancer) in a subject in need of such treatment, the method comprisingadministering to the subject a therapeutically effective amount of acompound of Formula I or pharmaceutically acceptable salt or solvatethereof. For example, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising a) detecting a dysregulation of a FGFR gene, a FGFRkinase, or the expression or activity or level of any of the same in asample from the subject; and b) administering a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof. In some embodiments, thedysregulation of a FGFR gene, a FGFR kinase, or the expression oractivity or level of any of the same includes one or more fusionproteins. Non-limiting examples of FGFR gene fusion proteins aredescribed in Table BA. In some embodiments, the fusion protein isFGFR3-TACC3. In some embodiments, the dysregulation of a FGFR gene, aFGFR kinase, or the expression or activity or level of any of the sameincludes one or more FGFR kinase protein point mutations/insertions.Non-limiting examples of FGFR kinase protein pointmutations/insertions/deletions are described in Table BC. In someembodiments, the FGFR1 kinase protein pointmutations/insertions/deletions are selected from the group consisting ofT141R, R445W, N546K, V561M, K656E, and G818R. In some embodiments, theFGFR2 kinase protein point mutations/insertions/deletions are selectedfrom the group consisting of S252W, P253R, A315T, D336N, Y375C, C382R,V395D, D471N, 1547V, N549K, N549Y, V565I, V565F, and K659E. In someembodiments, the FGFR3 kinase protein pointmutations/insertions/deletions are selected from the group consisting ofS131L, R248C, S249C, G370C, S371C, Y373C, G380R, R399C, E627K, K650E,K650M, V555M, V554L, V677I, and D785Y. In some embodiments, the FGFR4kinase protein point mutations/insertions/deletions are selected fromthe group consisting of R183S, R434Q, D425N in FGFR4 isoform 2, V550L,and R610H. In some embodiments, the FGFR kinase protein pointmutations/insertions/deletions occur in a FGFR fusion protein (e.g., anyof the FGFR gene fusion proteins described in Table BA).

A dysregulation of a FGFR gene, a FGFR protein, or expression oractivity, or level of the same, can, e.g., include a mutation(s) in aFGFR1, FGFR2, FGFR3, or FGFR4 gene that results in a FGFR1, FGFR2,FGFR3, or FGFR4 protein containing at least one (e.g., two, three, four,or five) point mutations (e.g., one of more of the point mutationslisted in Table BC or Table BD).

A dysregulation of a FGFR gene, a FGFR protein, or expression oractivity, or level of the same, can be a mutation in a FGFR1, FGFR2,FGFR3, or FGFR4 gene that results in a deletion of one or morecontiguous amino acids (e.g., at least two, at least three, at leastfour, at least 5, at least 6, at least 7, at least 8, at least 9, atleast 10, at least 15, at least 20, at least 30, at least 40, at least50, at least 60, at least 70, at least 80, at least 90, at least 100, atleast 110, at least 120, at least 130, at least 140, at least 150, atleast 160, at least 170, at least 180, at least 190, at least 200, atleast 210, at least 220, at least 230, at least 240, at least 250, atleast 260, at least 270, at least 280, at least 290, at least 300, atleast 310, at least 320, at least 330, at least 340, at least 350, atleast 360, at least 370, at least 380, at least 390, or at least 400amino acids) in the FGFR1, FGFR2, FGFR3, or FGFR4 protein (except forthe deletion of amino acids in the kinase domain of FGFR1, FGFR2, FGFR3,or FGFR4 that would result in inactivation of the kinase domain).

In some examples, a dysregulation of a FGFR gene, a FGFR protein, orexpression or activity, or level of the same, can include an alternatespliced form of a FGFR mRNA. In some examples, a dysregulation of a FGFRgene, a FGFR protein, or expression or activity, or level of the same,includes an amplification of a FGFR gene (e.g., one, two, three, or fouradditional copies of a FGFR1, FGFR2, FGFR3, and/or FGFR4 gene) that canresult, e.g., in an autocrine expression of a FGFR gene in a cell.

In some embodiments of any of the methods or uses described herein, thecancer (e.g., FGFR-associated cancer) is a hematological cancer. In someembodiments of any of the methods or uses described herein, the cancer(e.g., FGFR-associated cancer) is a solid tumor. In some embodiments ofany of the methods or uses described herein, the cancer (e.g.,FGFR-associated cancer) is a lung cancer (e.g., small cell lungcarcinoma, non-small cell lung carcinoma, squamous cell carcinoma, lungadenocarcinoma, large cell carcinoma, mesothelioma, lung neuroendocrinecarcinoma, smoking-associated lung cancer), prostate cancer, colorectalcancer (e.g., rectal adenocarcinoma), endometrial cancer (e.g.,endometrioid endometrial cancer, endometrial adenocarcinoma), breastcancer (e.g., hormone-receptor-positive breast cancer, triple-negativebreast cancer, neuroendodrine carcinoma of the breast), skin cancer(e.g., melanoma, cutaneous squamous cell carcinoma, basal cellcarcinoma, large squamous cell carcinoma), gallbladder cancer,liposarcoma (e.g., dedifferentiated liposarcoma, myxoid liposarcoma),pheochromocytoma, myoepithelial carcinoma, urothelial carcinoma,spermatocytic seminoma, stomach cancer, head and neck cancer (e.g., headand neck (squamous) carcinoma, head and neck adenoid cysticadenocarcinoma), brain cancer (e.g., glialneural tumors, glioma,neuroblastoma, glioblastoma, pilocytic astrocytoma, Rosette formingglioneural tumor, dysembryoplastic neuroepithelial tumor, anaplasticastrocytoma, medulloblastoma, ganglioglioma, oligodendroglioma),malignant peripheral nerve sheath tumor, sarcoma (e.g., soft tissuesarcoma (e.g., leiomyosarcoma), osteosarcoma), esophageal cancer (e.g.,esophageal adenocarcinoma), lymphoma, bladder cancer (e.g., bladderurothelial (transition cell) carcinoma), cervical cancer (e.g., cervicalsquamous cell carcinoma, cervical adenocarcinoma), fallopian tube cancer(e.g., fallopian tube carcinoma), ovarian cancer (e.g., ovarian serouscancer, ovarian mucinous carcinoma), cholangiocarcinoma, adenoid cysticcarcinoma, pancreatic cancer (e.g., pancreatic exocrine carcinoma,pancreatic ductal adenocarcinoma, pancreatic cancer intraepithelialneoplasia), salivary gland cancer (e.g., pleomorphic salivary glandadenocarcinoma, salivary adenoid cystic cancer), oral cancer (e.g., oralsquamous cell carcinoma), uterine cancer, gastric or stomach cancer(e.g., gastric adenocarcinoma), gastrointestinal stromal tumors, myeloma(e.g., multiple myeloma), lymphoepithelioma, anal cancer (e.g., analsquamous cell carcinoma), prostate cancer (e.g., prostateadenocarcinoma), renal cell carcinoma, thymic cancer, gastroesophogealjunction adenocarcinoma, testicular cancer, rhabdomyosarcoma (e.g.,alveolar rhabdomyosarcoma, embryonic rhabomyosarcoma), renal papillarycarcinoma, liver cancer (e.g., hepatocellular carcinoma, intrahepaticcholangiocarcinoma), carcinoid, myeloid proliferative disorders (alsocalled myeloid proliferative neoplasms (MPN); e.g., 8p11myeloproliferative syndrome (EMS, also called stem cellleukemia/lymphoma), acute myeloid leukemia (AML), chronic myeloidleukemia (CML)), lymphoma (e.g., T-cell lymphoma, T-lymphoblasticlymphoma, acute lymphoblastic leukemia (ALL), B-cell lymphoma), myeloidand lymphoid neoplasms, chronic neutrophilic leukemia, phosphaturicmesenchymal tumor, thyroid cancer (e.g. anaplastic thyroid carcinoma),or biliary duct cancer. Additional examples of FGFR-associated cancerare listed in Tables BA, BB, and BC.

In some embodiments of any of the methods or uses described herein, thecancer (e.g., FGFR-associated cancer) is selected from the group of:acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), cancerin adolescents, adrenocortical carcinoma, anal cancer, appendix cancer,astrocytoma, atypical teratoid/rhabdoid tumor, basal cell carcinoma,bile duct cancer, bladder cancer, bone cancer, brain stem glioma, braintumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoidtumor, unknown primary carcinoma, cardiac tumors, cervical cancer,childhood cancers, chordoma, chronic lymphocytic leukemia (CLL), chronicmyelogenous leukemia (CML), chronic myeloproliferative neoplasms,neoplasms by site, neoplasms, colon cancer, colorectal cancer,craniopharyngioma, cutaneous T-cell lymphoma, cutaneous angiosarcoma,bile duct cancer, ductal carcinoma in situ, embryonal tumors,endometrial cancer, ependymoma, esophageal cancer,esthesioneuroblastoma, Ewing sarcoma, extracranial germ cell tumor,extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer,fallopian tube cancer, fibrous histiocytoma of bone, gallbladder cancer,gastric cancer, gastrointestinal carcinoid tumor, gastrointestinalstromal tumors (GIST), germ cell tumor, gestational trophoblasticdisease, glioma, hairy cell tumor, hairy cell leukemia, head and neckcancer, thoracic neoplasms, head and neck neoplasms, CNS tumor, primaryCNS tumor, heart cancer, hepatocellular cancer, histiocytosis, Hodgkin'slymphoma, hypopharyngeal cancer, intraocular melanoma, islet celltumors, pancreatic neuroendocrine tumors, Kaposi sarcoma, kidney cancer,Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oralcavity cancer, liver cancer, lung cancer, lymphoma, macroglobulinemia,malignant fibrous histiocytoma of bone, osteocarcinoma, melanoma, Merkelcell carcinoma, mesothelioma, metastatic squamous neck cancer, midlinetract carcinoma, mouth cancer, multiple endocrine neoplasia syndromes,multiple myeloma, mycosis fungoides, myelodysplastic syndromes,myelodysplastic/myeloproliferative neoplasms, neoplasms by site,neoplasms, myelogenous leukemia, myeloid leukemia, multiple myeloma,myeloproliferative neoplasms, nasal cavity and paranasal sinus cancer,nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-smallcell lung cancer, lung neoplasm, pulmonary cancer, pulmonary neoplasms,respiratory tract neoplasms, bronchogenic carcinoma, bronchialneoplasms, oral cancer, oral cavity cancer, lip cancer, oropharyngealcancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis,paraganglioma, paranasal sinus and nasal cavity cancer, parathyroidcancer, penile cancer, pharyngeal cancer, pheochromosytoma, pituitarycancer, plasma cell neoplasm, pleuropulmonary blastoma,pregnancy-associated breast cancer, primary central nervous systemlymphoma, primary peritoneal cancer, prostate cancer, rectal cancer,colon cancer, colonic neoplasms, renal cell cancer, retinoblastoma,rhabdomyosarcoma, salivary gland cancer, sarcoma, Sezary syndrome, skincancer, Spitz tumors, small cell lung cancer, small intestine cancer,soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer,stomach cancer, T-cell lymphoma, testicular cancer, throat cancer,thymoma and thymic carcinoma, thyroid cancer, transitional cell cancerof the renal pelvis and ureter, unknown primary carcinoma, urethralcancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer,and Wilms' tumor.

In some embodiments, a hematological cancer (e.g., hematological cancersthat are FGFR-associated cancers) is selected from the group consistingof leukemias, lymphomas (non-Hodgkin's lymphoma), Hodgkin's disease(also called Hodgkin's lymphoma), and myeloma, for instance, acutelymphocytic leukemia (ALL), acute myeloid leukemia (AML), acutepromyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL),chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML),chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia(AUL), anaplastic large-cell lymphoma (ALCL), prolymphocytic leukemia(PML), juvenile myelomonocyctic leukemia (JMML), adult T-cell ALL, AMLwith trilineage myelodysplasia (AML/TMDS), mixed lineage leukemia (MLL),myelodysplastic syndromes (MDSs), myeloproliferative disorders (MPD),and multiple myeloma (MM). Additional examples of hematological cancersinclude myeloproliferative disorders (MPD) such as polycythemia vera(PV), essential thrombocytopenia (ET) and idiopathic primarymyelofibrosis (IMF/IPF/PMF). In some embodiments, the hematologicalcancer (e.g., the hematological cancer that is a FGFR-associated cancer)is AML or CMML.

In some embodiments, the cancer (e.g., the FGFR-associated cancer) is asolid tumor. Examples of solid tumors (e.g., solid tumors that areFGFR-associated cancers) include, for example, lung cancer (e.g., lungadenocarcinoma, non-small-cell lung carcinoma, squamous cell lungcancer), bladder cancer, colorectal cancer, brain cancer, testicularcancer, bile duct cancer cervical cancer, prostate cancer, andsparmatocytic seminomas. See, for example, Turner and Grose, Nat. Rev.Cancer, 10(2):116-129, 2010.

In some embodiments, the cancer is selected from the group consisting ofbladder cancer, brain cancer, breast cancer, cholangiocarcinoma, headand neck cancer, lung cancer, multiple myeloma, rhabdomyosarcoma,urethral cancer, and uterine cancer. In some embodiments, the cancer isselected from the group consisting of lung cancer, breast cancer, andbrain cancer. In some embodiments, a FGFR1-associated cancer is selectedfrom the group consisting of lung cancer, breast cancer, and braincancer. In some embodiments, the cancer is selected from the groupconsisting of breast cancer, uterine cancer, cholangiocarcinoma, andlung cancer. In some embodiments, a FGFR2-associated cancer is selectedfrom the group consisting of breast cancer, uterine cancer,cholangiocarcinoma, and lung cancer. In some embodiments, the cancer isselected from the group consisting of lung cancer, bladder cancer,urethral cancer, multiple myeloma, and head and neck cancer. In someembodiments, a FGFR3-associated cancer is selected from the groupconsisting of lung cancer, bladder cancer, urethral cancer, multiplemyeloma, and head and neck cancer. In some embodiments, the cancer isselected from lung cancer, rhabdomyosarcoma, and breast cancer. In someembodiments, a FGFR4-associated cancer is selected from lung cancer,rhabdomyosarcoma, and breast cancer.

In some embodiments, the patient is a human.

Compounds of Formula I and pharmaceutically acceptable salts andsolvates thereof are also useful for treating a FGFR-associated cancer.

Accordingly, also provided herein is a method for treating a subjectdiagnosed with or identified as having a FGFR-associated disease ordisorder (e.g., a FGFR-associated cancer, e.g., any of the exemplaryFGFR-associated cancers disclosed herein), comprising administering tothe subject a therapeutically effective amount of a compound of FormulaI or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition thereof as defined herein.

Dysregulation of a FGFR kinase, a FGFR gene, or the expression oractivity or level of any (e.g., one or more) of the same can contributeto tumorigenesis. For example, a dysregulation of a FGFR kinase, a FGFRgene, or expression or activity or level of any of the same can be atranslocation, overexpression, activation, amplification, or mutation ofa FGFR kinase, a FGFR gene, or a FGFR kinase domain. Translocation caninclude a gene translocation resulting in the expression of a fusionprotein that includes a FGFR kinase domain and a fusion partner. Forexample, a fusion protein can have increased kinase activity as comparedto a wildtype FGFR protein. In some embodiments, a mutation in a FGFRgene can involve mutations in the FGFR ligand-binding site,extracellular domains, kinase domain, and in regions involved inproteimprotein interactions and downstream signaling. In someembodiments, a mutation (e.g., an activating mutation) in a FGFR genecan result in the expression of a FGFR kinase having one or more (e.g.,two, three, four, five, six, seven, eight, nine, or ten) amino acidsubstitutions (e.g., one or more amino acid substitutions in the kinasedomain (e.g., corresponding to amino acid positions 477-761 in SEQ IDNO. 1, amino acid positions 480-764 in SEQ ID NO. 3, or amino acidpositions 471-755 in SEQ ID NO. 5); a gatekeeper amino acid (e.g.,corresponding to amino acid position 561 in SEQ ID NO. 1, amino acidposition 564 in SEQ ID NO. 3, or amino acid position 555 in SEQ ID NO.5); the P-loop (e.g., corresponding to amino acid positions 484-491 inSEQ ID NO. 1, amino acid positions 487-494 in SEQ ID NO. 3, or aminoacid positions 478-485 in SEQ ID NO. 5); the DFG motif (e.g.,corresponding to amino acid positions 641-643 in SEQ ID NO. 1, aminoacid positions 644-646 in SEQ ID NO. 3, or amino acid positions 635-637in SEQ ID NO. 5); the activation loop (e.g., corresponding to amino acidpositions 640-665 in SEQ ID NO. 1, amino acid positions 643-668 in SEQID NO.3, or amino acid positions 634-659 in SEQ ID NO. 5); the C-helixand loop preceeding the C-helix (e.g., corresponding to amino acidpositions 524-545 in SEQ ID NO. 1, amino acid positions 527-548 in SEQID NO. 3, or amino acid positions 518-539 in SEQ ID NO. 5); and/or theATP binding site (e.g., corresponding to amino acid positions 487-489,562-565,627,628,630, and 641 in SEQ ID NO. 1, amino acid positions490-492,565-568,630,631,633, and 644 in SEQ ID NO. 3, or amino acidpositions 481-483,556-559,621,622,624, and 635 in SEQ ID NO. 5). In someembodiments, a mutation can be a gene amplification of a FGFR gene. Insome embodiments, a mutation (e.g., an activating mutation) in a FGFRgene can result in the expression of a FGFR kinase that lacks at leastone amino acid (e.g., at least 2, at least 3, at least 4, at least 5, atleast 6, at least 7, at least 8, at least 9, at least 10, at least 12,at least 14, at least 16, at least 18, at least 20, at least 25, atleast 30, at least 35, at least 40, at least 45, or at least 50 aminoacids) as compared to a wildtype FGFR protein. In some embodiments,dysregulation of a FGFR kinase can be increased expression (e.g.,increased levels) of a wildtype FGFR kinase in a mammalian cell due toaberrant cell signaling and/or dysregulated autocrine/paracrinesignaling (e.g., as compared to a control non-cancerous cell). In someembodiments, a mutation (e.g., an activating mutation) in a FGFR genecan result in the expression of a FGFR kinase that has at least oneamino acid (e.g., at least 2, at least 3, at least 4, at least 5, atleast 6, at least 7, at least 8, at least 9, at least 10, at least 12,at least 14, at least 16, at least 18, at least 20, at least 25, atleast 30, at least 35, at least 40, at least 45, or at least 50 aminoacids) inserted as compared to a wildtype FGFR protein. In someembodiments, dysregulation of a FGFR kinase can be increased expression(e.g., increased levels) of a wildtype FGFR kinase in a mammalian cell(e.g., as compared to a control non-cancerous cell), e.g., due toaberrant cell signaling and/or dysregulated autocrine/paracrinesignaling. Other dysregulations can include FGFR mRNA splice variants.In some embodiments, the wildtype FGFR protein is the exemplary wildtypeFGFR protein described herein.

In some embodiments, the dysregulation of a FGFR gene, a FGFR kinase, orexpression or activity or level of any of the same, includesoverexpression of wild-type FGFR kinase (e.g., leading to autocrineactivation). In some embodiments, the dysregulation of a FGFR gene, aFGFR kinase protein, or expression or activity or level of any of thesame, includes overexpression, activation, amplification, or mutation ina chromosomal segment comprising the FGFR gene or a portion thereof,including, for example, the kinase domain portion, or a portion capableof exhibiting kinase activity.

Several FGFR translocations have been identified to play a role indefects in development and in a wide range of malignancies, wherebychromosomal rearrangement results in a nucleic acid sequence encoding afusion protein that includes a kinase domain of a FGFR protein and anamino acid sequence from a partner protein. In some examples, fusionproteins are located in the cytosol, do not undergo lysosomaldegradation, are not susceptible to feedback inhibition, and arepermanently dimerized in the absence of ligand. Such translocations canlead to FGFR overexpression, permanent dimerization of the fusionprotein-FGFR complex, and continuous signaling. The mechanism ofproliferation is dependent on the type of fusion protein and seems to bedisease specific (Jackson C C, et al., Hum Pathol 2010; 41:461-476). Forexample, a t(4;14) intergenic translocation, bringing FGFR3 and theadjacent Multiple Myeloma SET domain (MMSET) gene under the control ofthe Ig heavy chain (IGH) promoter, has been identified in 10% to 20% ofmultiple myelomas and is associated with poor prognosis and dependenceupon FGFR signaling (Chesi M, et al., Nat Genet 1997; 16:260-264; QingJ, et al., J Clin Invest 2009; 119:1216-1229). FGFR3 translocations arerarely found in prodromal conditions of multiple myeloma, implicatingthese translocations in the conversion to full multiple myeloma.Additional examples of FGFR fusion proteins and the specificFGFR-associated cancers that they cause (or cause in part) are listed inTable BA. The expression of FGFR fusion proteins can, e.g., cause (orcause in part) cholangiocarcinoma, bladder cancer, lung cancer, andbreast cancer. Additional examples of FGFR fusion proteins are known inthe art.

In some embodiments, the dysregulation of a FGFR gene, a FGFR kinaseprotein, or expression or activity or level of any of the same, includesone or more chromosome translocations or inversions resulting in a FGFRgene fusion. In some embodiments, the dysregulation of a FGFR gene, aFGFR kinase protein, or expression or activity or level of any of thesame, is a result of genetic translocations in which the expressedprotein is a fusion protein containing residues from a non-FGFR partnerprotein, and includes a minimum of a functional FGFR kinase domain.

Non-limiting examples of FGFR fusion proteins are shown in Table BA.

TABLE BA FGFR Fusion Proteins Non-limiting Exemplary FGFR- FGFR Fusionpartner Associated Cancer(s) FGFR1 TACC1 Glioblastoma multiforme,Gastrointestinal stromal tumors¹³ FGFR1 FGFR1 Urothelial carcinoma FGFR1CNTRL Stem cell myeloproliferative disorders, EMS, AML, CML, T-celllymphoma FGFR1 FGFR1OP2 Myeloproliferative disorders, myeloproliferativedisorder stem cell leukemia/lymphoma syndrome, acute myeloid leukemia,8p11 myeloproliferative disorder³², AML, MPN FGFR1 FGFR1OP (also calledFOP) Myeloproliferative disorders, e.g., acute myeloid leukemia, T-celllymphoma, B-cell lymphoma, 8p11 myeloproliferative disorder,myeloproliferative disorder stem cell leukemia/lymphoma syndrome andlung cancer, myeloid and lymphoid neoplasms FGFR1 ZMYM2 (also calledRAMP, FIM, or Myeloproliferative disorder stem cell ZNF198)leukemia/lymphoma syndrome myeloid and lymphoid neoplasms, 8p11myeloproliferative disorder, Chronic neutrophilic leukemia²², ALL, CMD,T-lymphoblastic lymphoma, AML² FGFR1 CEP110 (also called CEP1 or Myeloidand lymphoid neoplasms; centriolin) 8p11 myeloproliferative disorder,Myeloproliferative disorder stem cell leukemia/lymphoma syndrome FGFR1BCR Myeloproliferative disorder stem cell leukemia/lymphoma syndrome,8p11 myeloproliferative disorder, AML, CML, ALL (e.g., B-ALL) FGFR1LRRFIP1 Myeloproliferative disorder stem cell leukemia/lymphomasyndrome, 8p11 myeloproliferative disorder, ALL, CMD, AML FGFR1 CPSF6Hematological Malignancies; 8p11 myeloproliferative disorder, CMD, MPN,AML, Myeloproliferative disorder stem cell leukemia/lymphoma syndromeFGFR1 BAG4 Lung squamous cell carcinoma, non- small cell lung cancerFGFR1 ERLIN2 Breast cancer FGFR1 TRIM24 (also called TIF1)Myeloproliferative disorder stem cell leukemia/lymphoma syndrome, 8p11myeloproliferative disorder, AML, MPN FGFR1 MYO18A Myeloproliferativedisorder stem cell leukemia/lymphoma syndrome, 8p11 myeloproliferativedisorder, MPN, AML FGFR1 HERV-K Myeloproliferative disorder stem cellleukemia/lymphoma syndrome, 8p11 myeloproliferative disorder, CMD, MPD,AML FGFR1 PLAG1 Head and neck cancer, pleomorphic salivary glandadenocarcinoma FGFR1 CUX1 Leukemia, lymphoma, 8p11 myeloproliferativedisorder, AML, MPN FGFR1 FOXO1 Rhabdomyosarcoma, alveolarrhabdomyosarcoma FGFR1 SQSTM1 Leukemia FGFR1 FN1 Phosphaturicmesenchymal tumor FGFR1 NUP98 8p11 myeloproliferative disorder FGFR1RANBP2 (also called NUP358) 8p11 myeloproliferative disorder, MPN, AMLFGFR1 TPR 8p11 myeloproliferative disorder, MPN, T-lymphoblasticlymphoma, MPN T-lymphoblastic lymphoma FGFR1 ZNF703 Breast cancer FGFR1NTM Bladder cancer, bladder urothelial (transition cell) carcinomaFGFR1¹ ZNF343 Osteosarcoma FGFR1³ FOP2 AML FGFR1⁷ OP2 AML FGFR1¹¹ TKDGlioma FGFR1¹⁵ ADAM32 Embryonal Rhabdomyosarcoma FGFR1¹⁷ EGFR Non-smallcell lung carcinoma FGFR1²⁷ ZNF577 Breast cancer FGFR1²⁸ ZNF791 FGFR1²⁸NDS3 (also called as WHSC1L1) Breast cancer²⁹ FGFR1²⁸ ADGRA2 (alsocalled as GPR124) FGFR1²⁸ RHOT1 Bladder cancer²⁹ FGFR1²⁹ ADAM18 Bladdercancer FGFR1²⁹ SLC20A2 Lung adenocarcinoma FGFR1³¹ RUNX1Myeloproliferative neoplasm³¹ FGFR1³⁷ USP6 Aneurysmal bone cyst FGFR1³⁸HOOK3 Gastrointestinal stromal tumor³⁸ FGFR2 CCAR2 Lung squamous cellcarcinoma FGFR2 CD44 Gastric cancer FGFR2 BICC1 Metastaticcholangiocarcinoma, cholangiocarcinoma, colorectal cancer,hepatocellular carcinoma, carcinoma of unknown primary FGFR2 SLC45A3Prostate cancer FGFR2 AFF3 Breast cancer FGFR2 CASP7 Breast cancer FGFR2CCDC6 Breast cancer, cholangiocarcinoma FGFR2¹⁶ KIAA1598 (also calledSHOOTIN1) Cholangiocarcinoma, intrahepatic cholangiocarcinoma FGFR2KIAA1967 Lung squamous cell cancer FGFR2 OFD1 Thyroid cancer FGFR2 CITLung adenocarcinoma FGFR2 AHCYL1 Cholangiocarcinoma FGFR2 PPHLN1Cholangiocarcinoma FGFR2 TACC3 Cholangiocarcinoma, intrahepaticcholangiocarcinoma FGFR2 MGEA5 Cholangiocarcinoma, intrahepaticcholangiocarcinoma FGFR2 FAM76A Ovarian cancer FGFR2 FRAG1 OsteosarcomaFGFR2 NPM1 Colorectal carcinoma (e.g., colorectal adenocarcinoma), largecell lung carcinoma FGFR2 TACC2 Cancer of unknown primary, gastriccancer, gastoesophageal junction adenocarcinoma FGFR2 C10orf68 Gastriccancer, gastroesophageal junction adenocarcinoma FGFR2 NCALD Breastcarcinoma FGFR2 NOL4 Cholangiocarcinoma FGFR2 PPAPDC1A Prostatecarcinoma FGFR2⁵ PARK2 Cholangiocarcinoma FGFR2⁵ ZDHHC6Cholangiocarcinoma FGFR2⁶ TXLNA Biliary tract cancer FGFR2⁶ KCTD1Biliary tract cancer FGFR2⁶ BICC1 type 2 Biliary tract cancer FGFR2⁸CCDC147 Cholangiocarcinoma FGFR2⁸ VCL Cholangiocarcinoma FGFR2⁹ BUB1Cholangiocarcinoma FGFR2⁹ CDCA8 Cholangiocarcinoma FGFR2⁹ DNAH5Cholangiocarcinoma FGFR2¹⁰ OGDH Anaplastic thyroid carcinoma FGFR2¹²CCDC3 Breast carcinoma FGFR2¹⁴ KIAA1217 Cholangiocarcinoma FGFR2¹⁸ INAGanglioma FGFR2¹⁹ IDH1 Cholangiocarcinoma FGFR2²³ WAC Hepatobiliarycancer FGFR2²³ OPTN Hepatobiliary cancer FGFR2²³ ZMYM4 Hepatobiliarycancer FGFR2²³ TBC1D1 Hepatobiliary cancer FGFR2²³ FRK Hepatobiliarycancer FGFR2²³ CREB5 Hepatobiliary cancer FGFR2²³ STK26 Hepatobiliarycancer FGFR2²⁴ TACC1 Intrahepatic cholangiocarcinoma FGFR2²⁵ PDHXGastric carcinoma FGFR2²⁵ COL14A1 Colorectal adenocarcinoma FGFR2²⁶PASD1 Oligodendrogliomaa FGFR2²⁸ ATE1 FGFR2²⁸ NSMCE4A FGFR2²⁹ USP10Ovarian cancer FGFR2³³ KLK2 Prostate cancer FGFR2³⁴ CEP55 Pancreaticintraductal tubulopapillary neoplasm FGFR2³⁴ SASS6 Pancreaticintraductal tubulopapillary neoplasm FGFR2³⁴ DISP1 Pancreaticintraductal tubulopapillary neoplasm FGFR2³⁵ GAB2 Esophagealadenocarcinoma FGFR2³⁶ ACSL5 Gastric cancer FGFR3 ELAVL3 Glioblastomamultiforme FGFR3 TACC3 Bladder cancer, oral cancer, head and necksquamous cell carcinoma, lung squamous cell carcinoma, cervicalcarcinoma or cancer, cervical adenocarcinoma, gallbladder cancer orcarcinoma, lung adenocarcinoma, non-small cell lung cancer, glioma,glioblastoma multiforme, carcinoma of unknown primary, endometrialadenocarcinoma, glioma, renal cell carcinoma, urothelial carcinoma,pancreatic exocrine carcinoma, urothelial carcinoma FGFR3 BAIAP2L1Bladder cancer, lung adenocarcinoma, lung squamous cell carcinoma FGFR3IGH Multiple myeloma FGFR3 MMSET Multiple myeloma FGFR3 TEL/ETV6 T-celllymphoma FGFR3 JAKMIP1 Bladder cancer, bladder urothelial (transitioncell) carcinoma, urothelial carcinoma FGFR3 TNIP2 Bladder urothelial(transition cell) carcinoma, urothelial carcinoma FGFR3 WHSC1 (alsocalled NSD2) Breast carcinoma, multiple myeloma³⁰ FGFR3 ADD1 Urothelialcarcinoma FGFR3⁴ RANBP17 Breast carcinoma FGFR3²⁰ TET2 Multiple myelomaFGFR3²¹ NBR1 Anaplastic astrocytoma FGFR3²¹ BRAP Glioblastoma multiformeFGFR3²⁹ AES Prostate adenocarcinoma FGFR3²⁹ TPRG1 Head and neck squamouscell carcinoma FGFR3³⁰ TET Multiple myeloma ¹Baroy et al., PloS One;11(9):e0163859. doi: 10.1371/journal.pone.0163859, 2016. ²Ren et al.,Int. 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FGFR gene amplification often leads to FGFR overexpression, which canprovoke ligand-independent signaling. In breast cancer, amplification ofthe genomic locus of FGFR1 (8p11-12) occurs in approximately 10% ofpredominantly estrogen receptor (ER)-positive patients (Taylor J G, etal., J Clin Invest 2009; 119:3395-4307). In vitro studies support thepotential oncogenic nature of FGFR1 amplification (Welm B E, et al., JCell Biol 2002; 157:703-14); however, due to the gene-dense nature ofthe 8p11-12 amplicon in breast cancer, there is continuing debate aboutthe identity of the driving oncogene. More recently, FGFR1 has beenfound to be amplified in 22% of squamous NSCLC (Weiss J, et al., SciTransl Med 2010; 2:62ra93), and these amplifications seem to conferdependence upon FGFR signaling. Unlike the broad amplicon containingFGFR1 found in breast cancers, the amplicon in lung is more focal; itremains to be seen if these differences influence the degree ofoncogenic addiction to FGFR1. FGFR2 amplifications have been reported inup to 10% of gastric cancers, most of which are diffuse-type withrelatively poor prognosis (Kunii K, et al., Cancer Res 2008;68:2340-2348). Further, in a FGFR2-amplified gastric cancer cell line,Snu-16, FGFR2 downregulation led to significant inhibition of cellgrowth and survival that further translated into tumor growth regressionin vivo (Xie L, et al., AZD4547, a potent and selective inhibitor ofFGF-receptor tyrosine kinases 1, 2 and 3, inhibits the growth ofFGF-receptor 2 driven gastric cancer models in vitro and in vivo. In:Proceedings of the American Association of Cancer Research AnnualMeeting; 2011 Apr. 2-6; Orlando (Fla.). Philadelphia (Pa.): AACR; 2011.Abstract nr 1643). In some gastric cancer cell lines, FGFR2amplification is accompanied by deletion of the coding exon locatedproximal to the C-terminus (Ueda T, et al., Cancer Res 1999;59:6080-6086). This deletion impedes receptor internalization, therebycontributing to constitutive activation of the receptor. The presence ofFGFR2 gene amplifications in gastric cancer is associated withsensitivity to inhibition of FGFR signaling by tyrosine kinaseinhibitors and monoclonal antibodies in preclinical models (Zhao G, etal., Mol Cancer Ther 2011; 10:2200-2210; Zhao W M, et al., Clin CancerRes 2010; 16:5750-5758). Non-limiting examples of FGFR-associatedcancers that are caused (or caused in-part) by the amplification and/oroverexpression of the FGFR1 gene, the FGFR2 gene, the FGFR3 gene, or theFGFR4 gene are listed in Table BB.

TABLE BB Overexpression or Amplification of FGFR Genes andFGFR-Associated Cancer FGFR1 Type of Dysregulation FGFR-AssociatedCancer Amplification or Breast cancer or carcinoma (e.g., hormonereceptor-positive breast cancer, ductal Overexpression carcinoma in situ(breast)), pancreatic ductal adenocarcinoma, pancreatic exocrinecarcinoma, smoking-associated lung cancer, small cell lung cancer, lungadenocarcinoma, non-small cell lung cancer, squamous cell lung cancer orcarcinoma, prostate cancer or carcinoma, ovarian cancer, fallopian tubecarcinoma, bladder cancer, rhabdomyosarcoma, head and neck carcinoma(e.g., head and neck squamous cell carcinoma), esophageal cancer (e.g.,esophageal squamous cell carcinoma), sarcoma (e.g., osteosarcoma),hepatocellular carcinoma, renal cell carcinoma, colorectal cancer (e.g.,colorectal adenocarcinoma), prostate cancer, salivary gland tumors,glioblastoma multiforme, urinary bladder cancer, urothelial carcinoma,carcinoma of unknown primary, squamous non-lung tumors, gastric cancer,gastroesophageal junction carcinoma, adenoid cystic carcinoma, analsquamous cell carcinoma, oral squamous cell carcinoma,cholangiocarcinoma, hemangioendothelioma, leiomyosarcoma, melanoma,neuroendocrine carcinoma, squamous cell carcinoma, uterinecarcinosarcoma FGFR2 Type of Dysregulation FGFR-Associated CancerAmplification Gastric cancer, gastroesophageal junction adenocarcinoma,breast cancer (e.g., triple- negative breast cancer), colon cancer,colorectal cancer (e.g., colorectal adenocarcinoma), urothelial cancer,bladder adenocarcinoma, carcinoma of unknown primary,cholangiocarcinoma, endometrial adenocarcinoma, esophagealadenocarcinoma, gallbladder carcinoma, ovarian cancer, fallopian tubecarcinoma, pancreatic exocrine carcinoma, sarcoma, squamous cellcarcinoma Overexpression Myxoid lipocarcinoma, rectal cancer, renal cellcarcinoma, breast cancer FGFR3 Type of Dysregulation FGFR-AssociatedCancer Upregulation of Colorectal cancer, hepatocellular carcinoma,pancreatic exocrine carcinoma Activity Overexpression Multiple myeloma,thyroid carcinoma, Amplification Bladder cancer and salivary adenoidcystic cancer, urothelial cancer, breast cancer, carcinoid, carcinoma ofunknown primary, colorectal cancer (e.g., colorectal adenocarcinoma),gallbladder carcinoma, gastric cancer, gastroesophageal junctionadenocarcinoma, glioma, mesothelioma, non-small cell lung carcinoma,small cell lung cancer, ovarian cancer, fallopian tube carcinoma,pancreatic exocrine carcinoma FGFR4 Type of DysregulationFGFR-Associated Cancer Amplification Rhabdomyosarcoma, prostate canceror carcinoma, breast cancer, urothelial cancer, carcinoid, carcinoma ofunknown primary, esophageal adenocarcinoma, head and neck carcinoma,hepatocellular carcinoma, non-small cell lung carcinoma, ovarian cancer,fallopian tube carcinoma, peritoneal carcinoma, renal cell carcinomaUpregulation of Colorectal cancer, hepatocellular carcinoma, adrenalcarcinoma, breast cancer Activity Overexpression Pancreaticintraepithelial neoplasia, and pancreatic ductal adenocarcinoma

FGFR mutations that confer constitutive activation have been describedin a number of congenital skeletal disorders (Turner N, Grose R., NatRev Cancer 2010; 10:116-129). FGFRs have been identified as among themost commonly mutated kinase genes in human cancers, with mutations inFGFR2 and FGFR3 being most prevalent (Turner N., Grose R., Nat RevCancer 2010; 10:116-129). For example, approximately 50% to 60% ofnon-muscle invasive and 17% of high-grade bladder cancers possess FGFR3mutations that cause constitutive FGFR dimerization and activation(Cappellen D. et al., Nat Genet 1999; 23:18-20). Activating andoncogenic FGFR2 mutations located in the extracellular and kinasedomains of the receptor have been described in 12% of endometrialcarcinomas (Dutt A. et al., Proc Natl Acad Sci USA 2008; 105:8713-8717).Importantly, the FGFR2 mutations found in endometrial cancer confersensitivity to FGFR inhibition (Dutt A. et al., Proc Natl Acad Sci USA2008; 105:8713-8717). More recently, FGFR2 mutations have been describedin 5% of squamous non-small cell lung cancers (NSCLC; Hammerman P. etal., Genomic characterization and targeted therapeutics in squamous celllung cancer [abstract]. In: Proceedings of the 14th World Conference onLung Cancer; 2011 3-7 Jul.; Aurora (CO): International Association forthe Study of Lung Cancer; 2011). FGFR3 mutations in bladder cancer andFGFR2 mutations in endometrial cancer are mutually exclusive withmutations in HRAS and KRAS, respectively. In addition, mutations in theFGFR4 kinase domain have been found in the childhood soft tissue sarcomarhabdomyosarcoma, causing autophosphorylation and constitutive signaling(Taylor J G, et al., J Clin Invest 2009; 119:3395-407). FGFR1, FGFR2,FGFR3, and/or FGFR4 can include one, two, three, four, five, six, seven,eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen,seventeen, eighteen, nineteen, or twenty different point mutations (ascompared to an appropriate corresponding wildtype FGFR1, FGFR2, FGFR3,or FGFR4 amino acid sequence, respectively). Non-limiting examples ofpoint mutations in FGFR1, FGFR2, FGFR3, or FGFR4 that are thought tocause (or cause in-part) a FGFR-associated cancer are listed in TableBC.

In some embodiments, the dysregulation of a FGFR gene, a FGFR kinase, orexpression or activity or level of any of the same, includes one or moredeletions (e.g., deletion of corresponding to amino acids 795-808 in SEQID NO:5), insertions, or point mutation(s) in a FGFR kinase. In someembodiments, the dysregulation of a FGFR gene, a FGFR kinase, orexpression or activity or level of any of the same, includes a deletionof one or more residues from the FGFR kinase, resulting in constitutiveactivity of the FGFR kinase domain. In some embodiments, thedysregulation of a FGFR gene, a FGFR kinase, or expression or activityor level of any of the same, includes at least one point mutation in aFGFR gene that results in the production of a FGFR kinase that has oneor more amino acid substitutions, insertions, or deletions as comparedto the wild-type FGFR kinase (see, for example, the point mutationslisted in Table BC or Table BD).

TABLE BC FGFR Point Mutations FGFR1 Amino acid Amino acid Amino acidposition position position Non-limiting (αA1 (αB1 (other ExemplaryNon-limiting Exemplary FGFR- isoform)^(1,A) isoform)^(1,B) isoform)mutation(s) Associated Cancer(s) 25 25 P25Q Lung cancer 70 70 G70RLung cancer, Lung squamous cell carcinoma 78 78 R78H Prostate cancer 7979 T79N⁴⁸ Colorectal cancer⁴⁸  87^(J) R87C⁶⁶ Cholangiocarcinoma⁶⁶ 93^(J) D93Y⁶⁸ Squamous cell lung cancer⁶⁸ 97 97 A97TEndometrioid endometrial cancer or endometrial cancer 107 107 S107L⁴⁸Colorectal cancer⁴⁸ 109^(J) S109N⁶⁶ Cholangiocarcinoma⁶⁶ 125 125 S125L,Breast cancer, skin cancer, Gallbladder c.373_374insTCAcancer, Dedifferentiated liposarcoma²⁴, /p.S125-Non-small cell lung carcinoma⁴⁰ E126insS⁴⁰ 126 126 P126S²Neuroendocrine carcinoma of the breast 127 127 D127E⁴⁹Pheochromocytoma⁴⁹ 140^(J) S140L⁵¹ Myoepithelial carcinoma⁵¹ 141 141T141R Lung cancer, Non-small cell lung carcinoma, Lung squamous cellcarcinoma, Endometrial adenocarcinoma, Urothelial carcinoma 150 150P150S Colorectal cancer 249 249 E249V⁷¹Exposure to nephrotoxin aristolochic acid⁷¹ 252 252 P252R, P252S,Skin cancer, melanoma, lung cancer, P252TLung adenocarcinoma, Spermatocytic seminoma 268 268 A2685Colorectal cancer, Stomach cancer 294^(J) A294T⁶⁶ Cholangiocarcinoma⁶⁶330 330 N330I Spermatocytic seminoma 334 334 E334QHead and neck squamous cell carcinoma 340 340 T340M⁴⁵Colon adenocarcinoma⁴⁵ 366 366 P366P⁵⁵ Lung adenocarcinoma⁵⁵ 374 374Y374C Spermatocytic seminoma 381 381 C381R Spermatocytic seminoma397^(J) p397L⁶⁶ Cholangiocarcinoma⁶⁶ 430 428 S430F Colorectal cancer 431429 A431S Colorectal cancer 445 443 R445WCutaneous squamous cell carcinoma 455^(J) R455C⁶⁶ Cholangiocarcinoma⁶⁶471 469 W471L Lung cancer 546 544 N546KBrain cancer or glioneural tumors, glioma, neuroblastoma, Malignantperipheral nerve sheath tumor, paraganglioma, glioblastoma, Pilocyticastrocytoma, Rosette forming glioneural tumor, Pineal tumor,Sarcoma, Dysembryoplastic neuroepithelial tumor¹⁹, (in vitro study) 561559 V561M^(25,26,30-32) (In vitro study) 563 561 Y563C³²(In vitro study) 569 567 L567T⁴¹ Glioneuronal tumor⁴¹ 576 574 R576WBrain cancer or glioneural tumors, glioblastoma, Spermatocytic seminoma598 596 K598N Esophageal adenocarcinoma 610 608 G610D Colorectal cancer614^(J) R614*⁶⁶ Cholangiocarcinoma⁶⁶ 654 652 Y654Y⁶⁵Intraheptatic cholangiocarcinoma⁶⁵ 655 653 K655I Pilocytic astrocytoma656 654 K656D, K656E, Brain cancer or glioneural tumors, K656M, K656Nglioma, glioblastoma, Pilocytic astrocytoma, Rosette formingglioneural tumor, Dysembryoplastic neuroepithelial tumor¹⁹ 661 659 R661PDysembryoplastic neuroepithelial tumor¹⁹ 658 656 T658PPilocytic astrocytoma 664 662 V664LLung cancer, Lung large cell carcinoma 668^(J) M668T⁶⁶Cholangiocarcinoma⁶⁶ 686^(J) K668N⁶⁶ Cholangiocarcinoma⁶⁶ 772 770P772S⁵⁹ Neurofibromatosis type 1⁵⁹ 788 786 C788Y⁴⁸ Colorectal cancer⁴⁸818 816 G818R Urothelial carcinoma 841^(J) H841Y⁶⁸Squamous cell lung cancer⁶⁸ Exon 1841 Exon 18 Glioneuronal tumo⁴¹inversion⁴¹ FGFR2 Amino acid Amino acid Amino acid position Non-limitingposition (IIIb position (IIIc (other ExemplaryNon-limiting Exemplary FGFR- isoform)^(1,C) isoform)^(1,D) isoform)mutation(s) Associated Cancer(s) 24 24 S24F Skin cancer, melanoma 57 57S57L⁵⁵ Ulcerative colitis patients at high risk ofcolorectal carcinoma (UCHR)⁷⁰ 71^(E) M71T³ Lymphoma, Bladder cancer 7373 T73N⁷² Squamous cell carcinoma⁷² 77 77 V77M Skin cancer, melanoma 9797 A97T Cervical cancer or cervical squamous cell carcinoma 98 98 T98T⁵⁵Lung adenocarcinoma⁵⁵ 101 101 D101Y Endometrioid endometrial cancer orendometrial cancer 104 104 L104P⁴⁴ Colon cancer⁴⁴ 116 116 E116KLung cancer, Lung adenocarcinoma 138 138 D138NLung cancer, Squamous cell lung cancer 142 142 D142V⁴⁵Rectal adenocarcinoma⁴⁵ 156 156 W156* Melanoma 160 160 E160ASkin cancer, melanoma 161 161 K161N⁶⁶ Cholangiocarcinoma⁶⁶ 186 186 M186TLymphoma, Bladder cancer 190 190 R190G Lung cancer 203 203 R203H, R203CColorectal cancer (e.g., colorectal adenocarcinoma), Breast cancer 210210 R210Q Colorectal cancer (e.g., colorectal adenocarcinoma) 211 211N211I Lung cancer, Squamous cell lung cancer, Endometrioid endometrialcancer or endometrial cancer 212 212 Q212KBrain Cancer, Gallbladder cancer 213 213 H213Y Skin cancer, melanoma 219219 E219K Skin cancer, melanoma 227 227 G227E Skin cancer, melanoma 232232 V232V⁵⁵ 247 247 D247Y Lung cancer, Squamous cell lung cancer 248 248V248D Skin cancer, melanoma 251 251 R251Q Skin cancer, melanoma 252 252S252W, S252L, Basal cell carcinoma, Breast Cancer, S252FOvarian cancer, Fallopian tube carcinoma, Cervical cancer or cervicalsquamous cell carcinoma, Squamous cell lung cancer, Endometrioidendometrial cancer or endometrial cancer, Spermatocytic seminoma 253 253P253L, P253R, Lung cancer, Lung adenocarcinoma, P253SSquamous cell lung cancer, Non-small cell lung cancer, Endometrioidendometrial cancer or endometrial cancer, Spermatocytic seminoma, Oralsquamous cell carcinoma 256 256 P256SCervical cancer or cervical squamous cell carcinoma 266 266A266_S267insST Non-small cell lung cancer³⁸ VVGGD³⁸ 267 267 S267PStomach cancer, Spermatocytic seminoma 271 271 G271E, G271G⁴⁶Skin cancer, melanoma, hepatocellular carcinoma⁴⁶ 272 272 G272VOvarian cancer or ovarian serous cancer 276 276 F276V, F276C⁶⁵Spermatocytic seminoma, intrahepatic cholangiocarcinoma⁶⁵ 278 278 C278FSpermatocytic seminoma 281 281 Y281C Spermatocytic seminoma 283 283D283N Lung cancer, Squamous cell lung cancer 288 288 I288S⁶²(tumor induced in mice)⁶² 289 289 Q289P Spermatocytic seminoma 290 290W290C, Lung cancer, Squamous cell lung W290R⁶²cancer, Endometrioid endometrial cancer or endometrial cancer,Spermatocytic seminoma, (tumor induced in mice)⁶² 290-291 290-291290_291WI > C Cholangiocarcinoma³⁸ (i.e., W290 and I291 replacedwith C)^(38,54) 292 292 K292M Exposure to nephrotoxin aristolochicacid⁷¹ 302 302 G302W⁴, Lung cancer, Squamous cell lung G302K⁴⁴cancer, colon cancer⁴⁴ 305 305 G305R Skin cancer, melanoma 310 310 K310REndometrioid endometrial cancer or endometrial cancer 314 A314DEndometrioid endometrial cancer or endometrial cancer 315 A315T, A315SColorectal cancer (e.g., colorectal adenocarcinoma), Lung cancer, Non-small cell lung cancer, Endometrioid endometrial cancer or endometrialcancer, Spermatocytic seminoma 320 S320C⁴Lung cancer, Squamous cell lung cancer 332 E332K⁶⁶ Cholangiocarcinoma⁶⁶334 336 D336N Colorectal cancer (e.g., colorectal adenocarcinoma) 336338 G338R Spermatocytic seminoma 338 340 Y340C, Y340HSpermatocytic seminoma 341 T341P Spermatocytic seminoma 340 342C342F, C342R, Spermatocytic seminoma C3425, C342W, C342Y 344A344G, A344P Spermatocytic seminoma 344 346 N346K⁶²(tumor induced in mice)⁶² 347 S347C Spermatocytic seminoma 352 354 S354CSpermatocytic seminoma 361 Q361R Colorectal cancer (e.g., colorectaladenocarcinoma) 371 370 T370R Melanoma 373 372 S372CEndometrioid endometrial cancer or endometrial cancer 376 375 Y375CAdenoid cystic carcinoma, Ovarian cancer or ovarian serous cancer,Endometrioid endometrial cancer or endometrial cancer, Pancreaticexocrine carcinoma, Spermatocytic seminoma 381 380 I380VLung cancer, Lung adenocarcinoma 383 382 C382REsophageal cancer, Lung cancer, Squamous cell lung cancer,Endometrioid endometrial cancer or endometrial cancer,Cholangiocarcinoma 390 389 A389T Endometrioid endometrial cancer orendometrial cancer 392 391 M391R Endometrioid endometrial cancer orendometrial cancer 393 392 V392A Oral squamous cell carcinoma 396 395V395D Salivary gland carcinoma, Endometrioid endometrial cancer orendometrial cancer 398 397 L397M Endometrioid endometrial cancer orendometrial cancer 400 399 R399Q⁶⁸ Squamous cell lung cancer⁶⁸ 406 405K405E Cervical cancer or cervical squamous cell carcinoma 421 420 K420ILung cancer, Lung adenocarcinoma 436 435 S435I⁷⁰Ulcerative colitis patients at high risk ofcolorectal carcinoma (UCHR)⁷⁰ 451 450 R450Q⁶⁸Squamous cell lung cancer⁶⁸ 459 458 P459fs⁴⁵ Colon adenocarcinoma⁴⁵ 463462 G462E Brain cancer, Spermatocytic seminoma 471 470 E470QLung cancer, Squamous cell lung cancer 472 471 D471N Gallbladder cancer475 474 W474X Skin cancer, melanoma 476 475 E475K Skin cancer, melanoma480 479 D479N Lung cancer, Lung adenocarcinoma 506 505 K505E⁷⁰Ulcerative colitis patients at high risk ofcolorectal carcinoma (UCHR)⁷⁰ 527 526 K526E Spermatocytic seminoma 531530 D530N Skin cancer, melanoma 536 535 M535I^(14,33)Endometrial cancer¹⁴, (in vitro study)³³ 538 537 M537I^(14,33)Lung cancer, Squamous cell lung cancer, Endometrial cancer¹⁴, (in vitrostudy)³³ 545 544 H544Q Lung cancer, Lung adenocarcinoma 548 547I547V³³, I547D Anaplastic astrocytoma, Endometrioidendometrial cancer or endometrial cancer, (in vitro study)³³ 549 548I548S⁶² (tumor induced in mice)⁶² 549/290 548/290 I548S/W290R(tumor induced in mice)⁶² 550 549 N549D, Head and neck squamous cellN549K^(14,33), carcinoma, Adenoid cystic carcinoma, N549Y,basal cell carcinoma, breast cancer, N549H^(14,28,33,34),Endometrioid endometrial cancer or N549S^(14,33),endometrial cancer, Uterine N549T⁶² carcinosarcoma, Spermatocyticseminoma, (in vitro study)^(33,34), uterinecancer²⁸, (tumor induced in mice)⁶² 550/310 549/310 K310R/N550K⁵²Endometrial carcinoma⁵² 552 551 L551IColorectal cancer (e.g., colorectal adenocarcinoma) 563 562 V562L²⁹(in vitro study)²⁹ 565 564 F5641^(14,28,33,34),Endometrial cancer¹⁴, (in vitro study)²⁹, V564F²⁹^(33,34), uterine cancer28 566 565 E565G^(14,28,33,34),Endometrial cancer¹⁴, (in vitro E565A⁵⁸, E565L⁶²study)^(33,34), uterine cancer²⁸, cholangiocarcinoma⁵⁸, (tumor inducedin mice)⁶² 569 568 S568L⁶² (tumor induced in mice)⁶² 569/563 568/562S568L/V562L⁶² (tumor induced in mice)⁶² 575 574 E574KSkin cancer, melanoma 583 582 P582L Colorectal cancer (e.g., colorectaladenocarcinoma) 584 583 G583W⁴, G583V Lung cancer, Lung adenocarcinoma,Squamous cell lung cancer 585 584 M584VCervical cancer or cervical squamous cell carcinoma 588 587 S587CBreast cancer 589 588 Y588D Cervical cancer or cervical squamouscell carcinoma 591 590 I590M Lung cancer, Lung adenocarcinoma 603 602D602E Lung cancer, Squamous cell lung cancer 613 612 R612TLung cancer, adenocarcinoma 618 617 L617M^(14,33),Endometrial cancer¹⁴, (in vitro study)³³, L617V⁵⁸ cholangiocarcinoma⁵⁸621 620 Q620K Lung cancer, Lung adenocarcinoma 626 625 R625TLung cancer, Lung adenocarcinoma 637 636 E636K Skin cancer, melanoma 641640 M640I Skin cancer, melanoma 642 641 K641R, K641N¹⁴Adenoid cystic carcinoma, Spermatocytic seminoma, Endometrial cancer¹⁴643 642 I642V Skin cancer, melanoma 649 648 A648T Skin cancer, melanoma660 659 K659M^(1,21,23), Salivary gland carcinoma, Brain cancer,K659N³⁴, Medulloblastoma, Pilocytic K659M^(17,28,34)astrocytoma, Breast cancer, Cervical cancer or cervical squamous cellcarcinoma, Lung cancer, Squamous celllung cancer, Endometrioid endometrial cancer or endometrial cancer,Spermatocytic seminoma, uterine cancer, Head and neck adenoid cysticcarcinoma, (in vitro study)³⁴, uterine cancer²⁸ 665 664 R664WColorectal cancer (e.g., colorectal adenocarcinoma) 689 688 S688FSkin cancer, melanoma 702 701 G701S Skin cancer, melanoma 709 708 P708SSkin cancer, melanoma 719 718 E718G^(14,33)Endometrial cancer¹⁴, (in vitro study)³³ 728 727 N727S⁷⁰Ulcerative colitis patients at high risk ofcolorectal carcinoma (UCHR)⁷⁰ 759 758 D758H⁴³ 760 759 R759X, R759QSkin cancer, melanoma 771 770 L770V Skin cancer, melanoma 770Y770IfsX14^(14,33) Endometrial cancer¹⁴, (in vitro study)³³ 773 772L772F Lung cancer, Squamous cell lung cancer 778 777 E777KColorectal cancer (e.g., colorectal adenocarcinoma) 779 778 Q778A⁴¹Glioneuronal tumor⁴¹ 787 786 T786K Lung cancer, Squamous cell lungcancer Exon 17 Exon 17 Exon 17 splice Ganglioglioma⁴² site mutation⁴²Splice site Gastric cancer¹³ mutation 940-2A > G¹³ Intron 17 Intron 17Urothelial cancer truncation⁵⁶ g.chr10: 123237608_123237Intrahepatic cholangiocarcinoma⁶⁵ 610delGAT⁶⁵ FGFR3 Amino acidAmino acid Amino acid position Non-limiting position (IIIbposition (IIIC (other Exemplary Non-limiting Exemplary FGFR-isoform)^(1,F) isoform)^(1,G) isoform) mutation(s) Associated Cancer(s)53 53 S53S⁶⁵ Intrahepatic cholangiocarcinoma⁶⁵ 64 64 P64P⁶⁵Intrahepatic cholangiocarcinoma⁶⁵ 79 79 T79SLung cancer, Lung adenocarcinoma 116 116 R116R⁵⁵ 121 121 F121Y⁴⁵Gastric adenocarinoma⁴⁵ 131 131 S131L, S131S⁵⁵Urothelial carcinoma, testicular cancer⁵⁵ 139 139 D139D⁵⁵ 192 192G192D⁶⁶ Cholangiocarncinoma⁶⁶ 196 196 R196R⁵⁵ Testicular cancer⁵⁵ 197197 G197S Multiple myeloma 201 201 I201I⁵⁵ 209 209 Q209HHead and neck cancer 216 216 E216K Bladder cancer 222 222 D222NBladder cancer 228 228 C228R Colorectal cancer 235 235 G235DBladder cancer 241 241 Y241C Multiple myeloma 248 248 R248C¹⁸, R248HCarcinoma of unknown primary, Gallbladder cancer, Cervical cancer,Head and neck cancer, Lung cancer, Non-small cell lung carcinoma,Squamous cell lung cancer, Urothelial carcinoma, Lymphoepithelioma,Multiple myeloma, Bladder cancer, Spermatocytic seminoma, Sarcoma,Seborrheic keratosis, Bladder cancer¹⁸ 249 249 S249C¹⁶Carcinoma of unknown primary, Anal squamous cell carcinoma, Gallbladdercancer, Cervical cancer, Head and neckcancer, Lung cancer, Non-small cell lung carcinoma, Squamous cell lungcancer, Urothelial carcinoma, Cervical cancer, Multiple myeloma, Bladdercancer, Prostate cancer, Spermatocytic seminoma, Renal cell carcinoma,Pancreatic exocrine carcinoma, Seborrheic keratosis, Breast cancer¹⁶,Exposure to nephrotoxin aristolochic acid⁷¹ 248/249 248/249R248C/S249C⁶⁰ Bladder cancer⁶⁰ 250 250 P250RMultiple myeloma, Spermatocytic seminoma 270 270 D270N⁶⁹Bladder cancer⁶⁹ 283 283 P283S Bladder cancer 286 286 Q286R⁶⁴Gastric cancer⁶⁴ 299 299 G299S³⁹ Bladder cancer³⁹ 306 306 V306IBladder cancer 320 D320N⁴⁴ Colon cancer⁴⁴ 320 E320*⁶⁴ Gastric cancer⁶⁴322 E322K Colorectal cancer 330 T330T⁵⁵ 338 T338M⁵⁵ 341 A341TEsophageal cancer or esophageal adenocarcinoma 349 H349Y Bladder cancer352 A352E⁴⁴ Colon cancer⁴⁴ 370 368 E368K Spermatocytic seminoma 372 370G370C Gallbladder cancer, Cervical cancer,Lung cancer, Non-small cell lung carcinoma, Squamous cell lung cancer,Urothelial carcinoma, Multiple myeloma, Bladder cancer,Spermatocytic seminoma, Cutaneous squamous cell carcinoma, Seborrheickeratosis 373 371 S371C Multiple myeloma, Bladder cancer,Spermatocytic seminoma, Cutaneous squamous cell carcinoma, Seborrheickeratosis 374 372 V372C³⁹ Bladder cancer³⁹ 375 373 Y373CGallbladder cancer, Urothelial carcinoma, Multiple myeloma, Bladdercancer, Spermatocytic seminoma, Thymic cancer 377 375 G375CSpermatocytic seminoma 381 379 Y379C Bladder cancer 382 380 G380R, G380EAnal squamous cell carcinoma, Gallbladder cancer, Multiple myeloma,Bladder cancer, Spermatocytic seminoma, Urothelial carcinoma 248/382248/380 R248C/G380R⁶⁰ Bladder cancer⁶⁰ 384 382 G382D Multiple myeloma386 384 F384L²⁰ Multiple myeloma, Bladder cancer, Prostate cancer²⁰,Pheochromocytoma⁴⁹ 388 386 F386L²⁰ Head and neck cancer, Prostatecancer²⁰ 378 376 I376C Bladder cancer 392 390 V390L⁶⁷Lung adenocarcinoma⁶⁷ 393 391 A393EUrothelial carcinoma, Bladder cancer, Prostate cancer, Spermatocyticseminoma, Seborrheic keratosis 401 399 R399C, R399H⁶⁴Gastric cancer, gastroesophageal junction adenocarcinoma, Carcinomaof unknown primary, Colorectal cancer, gastric cancer⁶⁴ 400 S400fs⁴⁸Colorectal cancer⁴⁸ 413 411 V411M³⁹ Bladder cancer³⁹ 415 413 K413NHead and neck cancer 416 414 I414I⁵⁵ Lung cancer⁵⁵ 422 420 K420R⁶⁶Cholangiocarcinoma⁶⁶ 431 429 A431T⁴⁵ Colon adenocarcinoma⁴⁵ 435 433S433C Lung cancer, Squamous cell lung cancer, Multiple myeloma 443 441A441T Multiple myeloma 447 445 S445L⁴⁸ Colorectal cancer⁴⁸ 454 452 A452SMultiple myeloma 468 466 E466K Brain cancer, Glioblastoma 542 540N540S, N540K, Bladder cancer, Spermatocytic N540T, N540V seminoma 557555 V555M³⁷ KMS-11 myeloma cell line derivative³⁷ 571 569 A569V⁴⁴Colon cancer⁴⁴ 587 585 P585T⁷⁰Ulcerative colitis patients at high risk ofcolorectal carcinoma (UCHR)⁷⁰ 605 603 R603Q Glioblastoma 619 617 D617GHead and neck cancer 629 627 E627K Sarcoma 632 630 V630MHead and neck cancer 636 634 A634T⁷⁰Ulcerative colitis patients at high risk ofcolorectal carcinoma (UCHR)⁷⁰ 646 644 N644D⁵³ Melanoma⁵³ 648 646D646Y, D646N⁵⁵ Mesothelioma, Bladder cancer, Lungsquamous cell carcinoma⁵⁵ 652 650 K650M²⁴, K650E,Gallbladder cancer, Cervical cancer, K650Q, K650N,Testicular cancer, Glioma, Head and K650Tneck cancer, Colorectal cancer, Lungcancer, Non-small cell lung carcinoma,Squamous cell lung cancer, Urothelialcarcinoma, Cervical cancer, Multiple myeloma, Bladder cancer, Lymphoma,Spermatocytic seminoma, Seborrheic keratosis, Dedifferentiatedliposarcoma²⁴ 382/652 380/650 G380R/K650N⁶⁰ Bladder cancer⁶⁰ 653 651T651I⁴⁴ Colon cancer⁴⁴ 677 675 S675S Urothelial carcinoma⁵⁷ 679 677V677I Endometrial adenocarcinoma 684 682 V682I⁷⁰Ulcerative colitis patients at high risk ofcolorectal carcinoma (UCHR)⁷⁰ 688 686 E686C Head and neck cancer 693 691G691R⁵⁰ Lung adenocarcinoma⁵⁰ 699 697 G697CGallbladder cancer, Head and neck cancer, Spermatocytic seminoma, Oralsquamous cell cancer 717 715 K715M Lung cancer, Squamous cell lungcancer 719 717 A717T Multiple myeloma, Colorectal cancer48 723 721H721R⁷⁰ Ulcerative colitis patients at high risk ofcolorectal carcinoma (UCHR)⁷⁰ 728 726 I726F Multiple myeloma 746746_747insG Urothelial carcinoma⁵⁷ 769 767 F767L⁶⁶ Cholangiocarcinoma⁶⁶787 785 D785Y, Carcinoma of unknown primary, Non- c.2349_2350de1small cell lung carcinoma⁴⁰ AG/p.D785fs*31⁴⁰ 796 794 L794RMultiple myeloma 797 795 P795A⁴ Multiple myeloma⁴ Deletion ofDeletion of Multiple myeloma⁶³ amino acids amino acids 797-810⁶³795-808⁶³ 799 797 A797P Urothelial carcinoma⁵⁷ 809 (stop) 807 (stop)807R^(9,10), 807C, Multiple myeloma, Spermatocytic 807G, 807T seminomaFGFR4 Amino acid Amino acid position Amino acid position Non-limiting(P22455- position (other Exemplary Non-limiting Exemplary FGFR- 1)^(1,H)(P22455-2)^(1,I) isoform) mutation(s) Associated Cancer(s) 10 10V10L⁴⁷, V10I⁵⁵ Colorectal cancer⁴⁷ 54 54 R54R⁵⁵ 56 56 C56SRhabdomyosarcoma 59 59 R59W²² Lung cancer²² 72 72 R72L Rhabdomyosarcoma122 122 T122A Rhabdomyosarcoma 136 136 P136L⁴⁷ Colorectal cancer⁴⁷ 137137 S137S⁵⁵ Ovarian mucinous carcinoma⁵⁵ 144 144 Q144EBrain cancer, Glioblastoma, Lung cancer, Lung squamous cell carcinoma163 163 P163P⁵⁵ Renal papillary carcinoma⁵⁵ 175 175 A175TRhabdomyosarcoma 179 179 T179A⁵⁵ Colorectal adenocarcinoma⁵⁵ 183 183R183S Lung cancer, Non-small cell lung carcinoma, Lung adenocarcinoma197 197 I197T⁴⁸ Colorectal cancer⁴⁸ 202 202 L202L⁵⁵ Melanoma⁵⁵ 228 228N228N⁵⁵ Renal chromophobe⁵⁵ 232 232 S232ILung cancer, Lung adenocarcinoma 234 234 R234H, R234R⁵⁵ Rhabdomyosarcoma240^(K) R240S⁷¹ Exposure to nephrotoxin aristolochic acid⁷¹ 241^(K)R241W⁷¹ Exposure to nephrotoxin aristolochic acid⁷¹ 257 257 A257T⁶⁶Cholangiocarcinoma⁶⁶ 326 326 E326K Breast cancer 334 334 L334L⁵⁵Lung squamous cell carcinoma⁵⁵ 352 352 P352P⁵⁵Colorectal adenocarcinoma⁵⁵ 367 Y367C Breast cancer 386 G386S⁵⁵Lung adenocarcinoma⁵⁵ 388 G388R³⁶, Bladder cancer, Stomach cancer, SkinG388A⁶¹ cancer, Prostate cancer, Head and necksquamous cell carcinoma, Liver cancer,Colorectal cancer (e.g., colorectal adenocarcinoma), Breast cancer³⁶,Mammary carcinoma, Lung cancer, Sarcoma (e.g., soft tissue sarcoma,Ewing sarcoma⁶¹), Rhabdomyosarcoma 434 394 R394QBrain cancer, Glioblastoma, Liver cancer, Lung cancer, Lung squamouscell carcinoma 425 D425N Carcinoid 484 444 A484T Breast cancer 516 476D516N⁵⁵ Lung adenocarcinoma⁵⁵ 535 495 N535D, N535K Rhabdomyosarcoma 550510 V550M, V550E, Breast cancer, Rhabdomyosarcoma, V550LNeuroendocrine carcinoma of the breast 553 513 A553A⁵⁵ 554 514 A554VRhabdomyosarcoma 568 528 P568Q²² Lung cancer²² 576 536 G576DRhabdomyosarcoma 583 543 P583Q Colorectal cancer (e.g., colorectaladenocarcinoma) 610 570 R610H Prostate cancer 614 574 A614SColorectal cancer (e.g., colorectal adenocarcinoma) 616 576R616G, R616C⁴⁵ Lung cancer, Lung adenocarcinoma, cecum adenocarcinoma⁴⁵636 596 G636C¹⁵ Stomach cancer¹⁵ 671 631 D671NHead and neck squamous cell carcinoma 681 641 E681KLung cancer, Lung adenocarcinoma 712 672 P712TLung cancer, Lung adenocarcinoma 716 676 P716R Skin cancer 729 689 A729GLung cancer, Lung adenocarcinoma 738 698 Q738K Lung cancer 772 732 S772NLung cancer, Lung neuroendocrine carcinoma ^(A)See UniParc entryUPI00000534B8 ^(B)See UniParc entry UPI0000001COF CSee UniParc entryUPI000002A99A ^(D)See UniParc entry UPI000012A72A ^(E)See UniParc entryUPI000059D1C2 ^(F)See UniParc entry UPI000002A9AC ^(G)See Uniparc entryUPI000012A72C ^(H)See Uniparc entry UPI000012A72D ^(I)See Uniparc entryUPI000013E0B8 ^(J)See Uniparc entry UPI00010E06A3 ^(K)See Genbank entryBAD92868.1 ¹Each isoform of FGFR1, FGFR2, FGFR3, and FGFR4 has adifferent length, and thus, the corresponding amino acid position in oneisoform of FGFR1, FGFR2, FGFR3, and FGFR4 may be different in anotherisoform of FGFR1, FGFR2, FGFR3, and FGFR4. The position of each pointmutation listed above in each isoform of FGFR1, FGFR2, FGFR3, and FGFR4can be identified by first identifying the isoform(s) of FGFR1, FGFR2,FGFR3, or FGFR4 which correspond to the specific point mutation listedabove (by amino acid position and starting amino acid), and thenaligning the amino acid sequence of identified isoform(s) of FGFR1,FGFR2, FGFR3, or FGFR4 with the amino acid sequences of the otherisoforms of FGFR1, FGFR2, FGFR3, or FGFR4. ²Ang et al., Diagn. Mol.Pathol. Feb. 24, 2014 (Epub ahead of print). ³U.S. Pat. App. PublicationNo. 2011/0008347. ⁴Gallo et al., Cytokine Growth Factor Rev. 26:425-449, 2015. ⁵Davies et al., J. Cancer Res. 65: 7591, 2005. ⁶Kelleheret al., Carcinogenesis 34: 2198, 2013. ⁷Cazier et al., Nat. Commun. 5:3756, 2014. ⁸Liu et al., Genet. Mol. 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Abstract Number: 11596, 2016 Annual Meeting of theAmerican Society of Clinical Oncology, Chicago, IL. ²³Nguyen et al.,Molecular Cancer Therapeutics, Vol. 14, No. 12, Supp.2, Abstract Number:C199, AACR-NCI-EORTC International Conference: Molecular Targets andCancer Therapeutics, 2015. ²⁴Li et al., Hum. Pathol., 55: 143-50, 2016.²⁵European Patent No. EP220344961. ²⁶Yoza et al., Genes Cells., (10):1049-1058, 2016. ²⁷U.S. Pat. No. 9,254,28862. ²⁸European PatentApplication Publication No. 3023101A1. ²⁹PCT Application Publication No.WO 2015/099127A1. ³⁰European Patent No. EP220344961. ³¹Yoza et al.,Genes Cells., (10): 1049-1058, 2016. ³²Bunney et al., EbioMedicine,2(3): 194-204, 2015. ³³Byron et al., Neoplasia, 15(8): 975-88, 2013.³⁴European Patent Application Publication No. EP3023101A1. ³⁵PCTApplication Publication No. WO 2015/099127A1. ³⁶Thussbas et al., J.Clin. 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PMID: 11157491. Note that the deletion of FGFR3 isoform IIIcresidues 795-808 also deletes the stop codon, elongating the protein by99 amino acids(ATGPQQCEGSLAAHPAAGAQPLPGMRLSADGETATQSFGLCVCVCVCVCVCTSACACVRAHLASRCRGTLGVPAAVQRSPDWCCSTEGPLFWGDPVQNVSGPTRWDPVGQGAGPDMARPLPLHHGTSQGALGPSHTQS).⁶⁴Ge, et al, Am J Cancer Res. 7(7): 1540-1553, 2017. PMID: 28744403⁶⁵Jiao et al, Nat Genet, 45(12): 1470-1473, 2013. doi: 10.1038/ng.2813⁶⁶Jusakul et al, Cancer Discov. 7(10): 1116-1135, 2017. doi:10.1158/2159-8290.CD-17-0368 ⁶⁷Guyard et al, Respir Res., 18(1): 120,2018. doi: 10.1186/s12931-017-0605-y ⁶⁸Paik et al, Clin Cancer Res.,23(18): 5366-5373, 2017. doi: 10.1158/1078-0432.CCR-17-0645 ⁶⁹Roy et al,Mod Pathol., 30(8): 1133-1143, 2017. doi: 10.1038/modpathol.2017.33⁷⁰Chakrabarty et al, Br J Cancer, 117(1): 136-143, 2017. doi:10.1038/bjc.2017.148 ⁷¹Hoang et al, Sci Transl Med., 5(197): 197ra102.doi: 10.1126/scitranslmed.3006200 ⁷²Kim et al, Ann Oncol., 28(6):1250-1259. doi: 10.1093/annonc/mdx098

Point mutations in FGFR1, FGFR2, FGFR3, and FGFR4 have been identifiedto result in resistance of a cancer cell to a FGFR inhibitor.Non-limiting examples of these mutations are depicted in Table BC. Insome embodiments, a FGFR-associated disorder (e.g., any of the cancersdescribed herein) can have one or more of the point mutations listed inTable BC. Also provided herein are methods of treating a subject thatinclude identifying a subject having one or more of the point mutationslisted in Table BC, and administering to the identified subject atherapeutically effective amount of a compound of Formula I (e.g., anyof the exemplary compounds described herein), or a pharmaceuticallyacceptable salt or solvate thereof. Also provided are methods oftreating a subject that include administering to a subject identified ashaving one or more of the point mutations listed in Table BC atherapeutically effective amount of a compound of Formula I (e.g., anyof the exemplary compounds described herein).

The term “mammal” as used herein, refers to a warm-blooded animal thathas or is at risk of developing a disease described herein and includes,but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters,and primates, including humans.

The phrase “time of survival” means the length of time between theidentification or diagnosis of cancer (e.g., any of the cancersdescribed herein) in a subject or patient by a medical professional andthe time of death of the subject or patient (caused by the cancer).Methods of increasing the time of survival in a subject or patienthaving a cancer are described herein.

In some embodiments, the dysregulation of a FGFR gene, a FGFR kinase, orexpression or activity or level of any of the same, includes a splicevariation in a FGFR mRNA which results in an expressed protein that isan alternatively spliced variant of FGFR having at least one residuedeleted (as compared to the wild-type FGFR kinase) resulting in aconstitutive activity of a FGFR kinase domain.

A “FGFR kinase inhibitor” as defined herein includes any compoundexhibiting FGFR inhibition activity. In some embodiments, a FGFR kinaseinhibitor is selective for a FGFR kinase. Exemplary FGFR kinaseinhibitors can exhibit inhibition activity (IC₅₀) against a FGFR kinaseof less than about 1000 nM, less than about 500 nM, less than about 200nM, less than about 100 nM, less than about 50 nM, less than about 25nM, less than about 10 nM, or less than about 1 nM as measured in anassay as described herein. In some embodiments, a FGFR kinase inhibitorcan exhibit inhibition activity (IC₅₀) against a FGFR kinase of lessthan about 25 nM, less than about 10 nM, less than about 5 nM, or lessthan about 1 nM as measured in an assay as provided herein.

As used herein, a “first FGFR kinase inhibitor” or “first FGFRinhibitor” is a FGFR kinase inhibitor as defined herein, but which doesnot include a compound of Formula I or a pharmaceutically acceptablesalt or solvate thereof as defined herein. As used herein, a “secondFGFR kinase inhibitor” or a “second FGFR inhibitor” is a FGFR kinaseinhibitor as defined herein, but which does not include a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof asdefined herein. When both a first and a second FGFR inhibitor arepresent in a method provided herein, the first and second FGFR kinaseinhibitor are different.

In some embodiments, the dysregulation of a FGFR gene, a FGFR kinase, orexpression or activity or level of any of the same, includes at leastone point mutation in a FGFR gene that results in the production of aFGFR kinase that has one or more amino acid substitutions or insertionsor deletions in a FGFR gene that results in the production of a FGFRkinase that has one or more amino acids inserted or removed, as comparedto the wild-type FGFR kinase. In some cases, the resulting FGFR kinaseis more resistant to inhibition of its phosphotransferase activity byone or more first FGFR kinase inhibitor(s), as compared to a wildtypeFGFR kinase or a FGFR kinase not including the same mutation. Suchmutations, optionally, do not decrease the sensitivity of the cancercell or tumor having the FGFR kinase to treatment with a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof(e.g., as compared to a cancer cell or a tumor that does not include theparticular FGFR inhibitor resistance mutation). In addition, suchmutations, optionally, do not decrease the sensitivity of the cancercell or tumor having the FGFR kinase to treatment with a compound thatcan form a covalent bond with a cysteine residue in a FGFR protein or apharmaceutically acceptable salt or solvate thereof (e.g., as comparedto a cancer cell or a tumor that does not include the particular FGFRinhibitor resistance mutation). In such embodiments, a FGFR inhibitorresistance mutation can result in a FGFR kinase that has one or more ofan increased V_(max), a decreased K_(m) for ATP, and an increased K_(D)for a first FGFR kinase inhibitor, when in the presence of a first FGFRkinase inhibitor, as compared to a wildtype FGFR kinase or a FGFR kinasenot having the same mutation in the presence of the same first FGFRkinase inhibitor.

In other embodiments, the dysregulation of a FGFR gene, a FGFR kinase,or expression or activity or level of any of the same, includes at leastone point mutation in a FGFR gene that results in the production of aFGFR kinase that has one or more amino acid substitutions as compared tothe wild-type FGFR kinase, and which has increased resistance to acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof, as compared to a wildtype FGFR kinase or a FGFR kinase notincluding the same mutation. In such embodiments, a FGFR inhibitorresistance mutation can result in a FGFR kinase that has one or more ofan increased V_(max), a decreased K_(m), and a decreased K_(D) in thepresence of a compound of Formula I or a pharmaceutically acceptablesalt or solvate thereof, as compared to a wildtype FGFR kinase or a FGFRkinase not having the same mutation in the presence of the same compoundof Formula I or a pharmaceutically acceptable salt or solvate thereof.

Examples of FGFR inhibitor resistance mutations can, e.g., include pointmutations, insertions, or deletions in and near the ATP binding site inthe tertiary structure of a FGFR kinase (e.g., corresponding to aminoacid positions 487-489,562-565,627,628,630, and 641 in SEQ ID NO. 1,amino acid positions 490-492, 565-568,630,631,633, and 644 in SEQ ID NO.3, or amino acid positions 481-483,556-559,621,622,624, and 635 in SEQID NO. 5) including but not limited to a gatekeeper residue (e.g., e.g.,corresponding to amino acid position 561 in SEQ ID NO. 1, amino acidposition 564 in SEQ ID NO. 3, or amino acid position 555 in SEQ ID NO.5), P-loop residues (e.g., corresponding to amino acid positions 484-491in SEQ ID NO. 1, amino acid positions 487-494 in SEQ ID NO. 3, or aminoacid positions 478-485 in SEQ ID NO. 5), residues in or near the DFGmotif (e.g., corresponding to amino acid positions 641-643 in SEQ ID NO.1, amino acid positions 644-646 in SEQ ID NO. 3, or amino acid positions635-637 in SEQ ID NO. 5). Additional examples of these types ofmutations include changes in residues that may affect enzyme activityand/or drug binding including but are not limited to residues in theactivation loop (e.g., corresponding to amino acid positions 640-665 inSEQ ID NO. 1, amino acid positions 643-668 in SEQ ID NO.3, or amino acidpositions 634-659 in SEQ ID NO. 5), residues near or interacting withthe activation loop, residues contributing to active or inactive enzymeconformations, changes including mutations, deletions, and insertions inthe loop proceeding the C-helix and in the C-helix (e.g., correspondingto amino acid positions 524-545 in SEQ ID NO. 1, amino acid positions527-548 in SEQ ID NO. 3, or amino acid positions 518-539 in SEQ ID NO.5). In some embodiments, the wildtype FGFR protein is the exemplarywildtype FGFR kinase described herein (e.g., any of SEQ ID NOs: 1-8).Specific residues or residue regions that may be changed (and are FGFRinhibitor resistance mutations) include but are not limited to thoselisted in Table BC and Table BD. In some embodiments, a FGFR inhibitorresistance mutation can be a mutation in a cysteine. In someembodiments, a FGFR inhibitor resistance mutation in a cysteine is aFGFR inhibitor resistance mutation in a cysteine that corresponds toCys582 of SEQ ID NO: 5. In some embodiments, a FGFR inhibitor resistancemutation in a cysteine is a FGFR inhibitor resistance mutation in acysteine that corresponds to Cys790 of SEQ ID NO:3. As can beappreciated by those skilled in the art, an amino acid position in areference protein sequence that corresponds to a specific amino acidposition in, e.g., SEQ ID NO: 1, can be determined by aligning thereference protein sequence with SEQ ID NO: 1 (e.g., using a softwareprogram, such as ClustalW2). A corresponding residue can be in adifferent isoform of the same FGFR (e.g., isoform IIIb of FGFR2 comparedto isoform IIIc of FGFR2), or in a different FGFR (e.g., in any isoformof FGFR3 compared to isoform IIIc of FGFR2). Additional examples of FGFRinhibitor resistance mutation positions are shown in Table BE. Changesto these residues may include single or multiple amino acid changes,insertions within or flanking the sequences, and deletions within orflanking the sequences. See also J. Kooistra, G. K. Kanev, O. P. J. VanLinden, R. Leurs, I. J. P. De Esch, and C. De Graaf, “KLIFS: Astructural kinase-ligand interaction database,” Nucleic Acids Res., vol.44, no. D1, pp. D365-D371,2016, which is incorporated by reference inits entirety herein.

Non-limiting examples of additional FGFR-associated diseases that arecaused by dysregulation of FGFR are listed in Table BD. A subject havingany of the additional FGFR-associated diseases described herein or knownin the art can be treated by administering to the subject atherapeutically effective amount of a compound of Formula I (e.g., anyof the exemplary compounds described herein).

TABLE BD Additional FGFR-associated diseases caused or caused in part byderegulation of a FGFR FGFR1 Amino acid Amino acid Non- Amino acidposition position limiting position (αA1 (αB1 (other ExemplaryNon-limiting Exemplary FGFR-Associated isoform)^(Z,A) isoform)^(Z,B)isoform) alteration(s) Condition(s)  4  4 W4C Kallman syndrome³⁷P33Afs*17³⁷ P33Afs*17³⁷ Kallman syndrome³⁷ Splice-site HypogonadotropicHypogonadism² mutation (c.91 + 2T > A)  48  48 G48S HypogonadotropicHypogonadism 2 with or without anosmia  58  58 R58Q⁴² Ichthyosisvulgaris and/or atopic dermatitis⁴²  70  70 G70R HypogonadotropicHypogonadism 2 with or without anosmia  77  77 N77K HypogonadotropicHypogonadism 2 with or without anosmia  78  78 R78C HypogonadotropicHypogonadism 2 with or without anosmia  96  96 S96C Kallman syndrome³⁷ 97  97 G97D Hypogonadotropic Hypogonadism 2 with or without anosmia,Kallman syndrome⁵⁰  99  99 Y99C Hypogonadotropic Hypogonadism 2 with orwithout anosmia, Kallman syndrome⁵⁰ 101 101 C101F HypogonadotropicHypogonadism 2 with or without anosmia 102 102 V102I HypogonadotropicHypogonadism 2 with or without anosmia 116 116 V116I HypogonadotropicHypogonadism 2 with or without anosmia 117 117 N117S HypogonadotropicHypogonadism 2 with or without anosmia 129 129 D129A HypogonadotropicHypogonadism 2 with or without anosmia 165 165 L165H Hartsfield Syndrome167 167 A167S Hypogonadotropic Hypogonadism 2 with or without anosmia,Kallman syndrome⁵⁰ 174 174 V174A Hypogonadotropic Hypogonadism 2 with orwithout anosmia 178 178 C178S Hypogonadotropic Hypogonadism 2 with orwithout anosmia, Kallman syndrome³⁹ 191 191 L191S Hartsfield Syndrome224 224 D224H Hypogonadotropic Hypogonadism 2 with or without anosmia228 228 Y228D Hypogonadotropic Hypogonadism 2 with or without anosmia237 237 G237D, Hypogonadotropic Hypogonadism 2 with or G237S withoutanosmia 239 239 I239T Hypogonadotropic Hypogonadism 2 with or withoutanosmia 244^(H) c.730_731in Craniosynostosis¹⁴ sG 245 245 L245PHypogonadotropic Hypogonadism 2 with or without anosmia 250 250 R250Q,Hypogonadotropic Hypogonadism 2 with or R250W without anosmia 252 252P252R Pfeiffer Syndrome^(1,8) 254 254 R254Q HypogonadotropicHypogonadism 2 with or without anosmia 261^(H) T261M Craniosynostosis¹⁴270 270 G270D Hypogonadotropic Hypogonadism 2 with or without anosmia273 273 V273M Hypogonadotropic Hypogonadism 2 with or without anosmia274 274 E274G Hypogonadotropic Hypogonadism 2 with or without anosmia277 277 C277Y Hypogonadotropic Hypogonadism 2 with or without anosmia283 283 P283R Hypogonadotropic Hypogonadism 2 with or without anosmia300 300 I300T Trigonocephaly 1 330 330 N330I Osteoglophonic Dysplasia332 332 S332C Hypogonadotropic Hypogonadism 2 with or without anosmia339 339 Y339C Hypogonadotropic Hypogonadism 2 with or without anosmia342 342 L342S Hypogonadotropic Hypogonadism 2 with or without anosmia343 343 A343V Hypogonadotropic Hypogonadism 2 with or without anosmia346 346 S346C Hypogonadotropic Hypogonadism 2 with or without anosmia348 348 G348R Hypogonadotropic Hypogonadism 2 with or without anosmia353^(E) A353T in Kallman syndrome³⁷ alternatively spliced exon 8A³⁷ 366366 P366L Hypogonadotropic Hypogonadism 2 with or without anosmia 374374 Y374C Osteoglophonic Dysplasia 381 381 C381R OsteoglophonicDysplasia 470 468 R470L Hypogonadotropic Hypogonadism 2 with or withoutanosmia 475 473 R473Q⁴¹ Congenital heart disease associated withambiguous genitalia⁴¹ 483 481 P483T Hypogonadotropic Hypogonadism 2 withor without anosmia 490 488 G480R Hartsfield Syndrome 520 518 A520THypogonadotropic Hypogonadism 2 with or without anosmia 538 536 I538VHypogonadotropic Hypogonadism 2 with or without anosmia 546 544 N546K³¹Encephalocraniocutaneous lipomatosis³¹ 607 605 V607M HypogonadotropicHypogonadism 2 with or without anosmia, Kallman syndrome⁵⁰ 618 616 K618NHypogonadotropic Hypogonadism 2 with or without anosmia 621 619 H621RHypogonadotropic Hypogonadism 2 with or without anosmia 622 620 R622G,Hypogonadotropic Hypogonadism 2 with or R622Q, without anosmia, Kallmansyndrome⁵⁰ R622*⁵⁰ 623 621 D623Y Hartsfield Syndrome 627 625 R627THartsfield Syndrome 628 626 N628K Hartsfield Syndrome 654 652 Y654*Kallman syndrome³⁷ 656 654 K656E³¹ Encephalocraniocutaneouslipomatosis³¹ 666 664 W666R Hypogonadotropic Hypogonadism 2 with orwithout anosmia 670 668 E670K Hypogonadotropic Hypogonadism 2 with orwithout anosmia, Kallman syndrome⁵⁰ 671 669 A671P HypogonadotropicHypogonadism 2 with or without anosmia 685 683 S685F HypogonadotropicHypogonadism 2 with or without anosmia 687 685 G687R HypogonadotropicHypogonadism 2 with or without anosmia 692 690 E692G HypogonadotropicHypogonadism 2 with or without anosmia 693 691 I693F HypogonadotropicHypogonadism 2 with or without anosmia 703 701 G703R, HypogonadotropicHypogonadism 2 with or G703S without anosmia 719 717 M719R,Hypogonadotropic Hypogonadism 2 with or M719V³⁷ without anosmia, Kallmansyndrome³⁷ 722 720 P722H, Hypogonadotropic Hypogonadism 2 with or P722Swithout anosmia, Kallman syndrome⁵⁰ 724 722 N724K HypogonadotropicHypogonadism 2 with or without anosmia 725 723 C725Y Hartsfield Syndrome745 743 P745S Hypogonadotropic Hypogonadism 2 with or without anosmia768 766 D768Y Hypogonadotropic Hypogonadism 2 with or without anosmia772 770 P772S Hypogonadotropic Hypogonadism 2 with or without anosmia,Ichthyosis vulgaris and/or atopic dermatitis⁴² 795 793 V795I⁴⁹Hypogonadotropic hypogonadism⁴⁹ FN1 fusion Tumor-induced osteomalacia(TIO)³⁸ FGFR2 Amino acid Non- Amino acid Amino acid position limitingposition (IIIb position (IIIc (other Exemplary Non-limiting ExemplaryFGFR-Associated isoform)^(Z,C) isoform)^(Z,D) isoform) alteration(s)Condition(s) 105 105 Y105C⁴⁵ Crouzon Syndrome⁴⁵ 172 172 A172F⁴⁵ Pfeiffersyndrome⁴⁵ 186 186 M186T⁴⁵ Apert Syndrome⁴⁵ 252 252 S252W, ApertSyndrome¹¹, Crouzon syndrome²⁰ S252L 253 253 P253R, ApertSyndrome^(11,45) P253L⁴⁵ 255 255 R255Q Ectrodactyly²⁵, Lethal PulmonaryAcinar Dysplasia²⁵ 267 267 S267P, Crouzon Syndrome^(10,46) S267F⁴⁶ 273273 p.273insE Crouzon syndrome²⁴ 276 276 F276V⁴⁵ Crouzon syndrome 278278 C278F, Crouzon Syndrome^(10,46) C278Y⁴⁶ 281 281 Y281C Crouzonsyndrome²⁴ 288 288 I288N⁴⁶ Crouzon syndrome⁴⁶ 289 289 Q289P CrouzonSyndrome¹⁰ 290 290 W290C, Craniosynostosis¹³, Crouzon syndrome^(22,46)W290R, W290G⁴⁶ 308 308 Y308C⁴⁶ Crouzon syndrome⁴⁶ 314 A314D⁴⁵ Pfeiffersyndrome⁴⁵ 315 A315S, Crouzon syndrome⁴⁵ A315T 315/252 A252L/A31Syndactyly⁴⁸ 5S⁴⁸ Nucleotides 958- Jackson-Weiss syndrome⁴⁶ 958-959959delAC⁴⁶ 321 D321A Pfeiffer Syndrome⁹, Craniosynostosis¹³ 328 Y328CCrouzon Syndrome¹⁰ 337 A337P⁴⁶ Crouzon syndrome⁴⁶ 338 G338R⁴⁵ Crouzonsyndrome⁴⁵ 340 Y340H, Crouzon Syndrome^(10,46), Craniosynostosis¹³Y340C, Y340S⁴⁶ 341 T341P Pfeiffer Syndrome⁹ 342 C342R, PfeifferSyndrome⁹, Crouzon Syndrome¹⁰, C342Y, Craniosynostosis¹³ C342S, C342F,C342W 344 A344G, Jackson-Weiss Syndrome¹², Crouzon A344A⁴⁶ syndrome⁴⁶347 S347C Crouzon Syndrome¹⁰, Jackson-Weiss syndrome²⁰ 354 S354C,Crouzon Syndrome^(10,46) S354F⁴⁶ 358 357 L357S⁴⁶ Crouzon syndrome⁴⁶ 373372 S372C Beare-Stevenson syndrome (BSS)²⁸ 376 375 Y375C Beare-Stevensonsyndrome (BSS)²⁸ 383 382 C382R Papillomatous pedunculated sebaceousnaevus (PPSN)²⁷ 385 384 G384R Craniosynostosis⁴⁷ 527 526 K526E⁴⁵ Crouzonsyndrome⁴⁵ 550 549 N549H, Craniosynostosis¹³, Crouzon syndrome^(20,45),N549T, Pfeiffer syndrome⁴⁵ N549D⁴⁵ N549K⁴⁵ 642 641 K641RCraniosynostosis¹³ 660 659 K695N⁴⁶ Crouzon syndrome⁴⁶ Atypical spliceApert syndrome²⁹ mutation (940-2A → G) FGFR3 Amino acid Non- Amino acidAmino acid position limiting position (IIIb position (IIIc) (otherExemplary Non-limiting Exemplary FGFR-Associated isoform)^(Z,F)isoform)^(Z,G) isoform) alteration(s) Condition(s)  84  84 S84LHypochondroplasia¹⁷ 200 200 R200C Hypochondroplasia¹⁷ 248 248 R248CThanatophoric dysplasia type I¹⁷, Seborrheic keratosis¹⁹ 248 248R248delinsL Thanatophoric dysplasia³⁰ C 250 250 P250R, Muenke CoronalCraniosynostosis P250L 262 262 N262H Hypochondroplasia¹⁷ 268 268 G268CHypochondroplasia¹⁷ 278 278 Y278C Hypochondroplasia¹⁷ 279 279 S279CHypochondroplasia¹⁷ 324 L324H Hypochondroplasia²¹ 329 V329I⁴⁴ Cleft lipand palate and microphthalmia⁴⁴ 328 N328I Hypochondroplasia⁷ 334 A334T⁴⁴Craniosynostosis⁴⁴ 344 S344C Achondroplasia³⁶ 346 G346E⁴⁷Achondroplasia⁴⁷ 348 S348C Achondroplasia³⁴ 372 370 G370C Thanatophoricdysplasia type I¹⁷ 373 371 S371C Thanatophoric dysplasia type I¹⁷ 375373 Y373C Thanatophoric dysplasia type I¹⁷ 377 375 G375C, AchondroplasiaG375R⁴⁷ 382 380 G380R Achondroplasia, Achondroplasia^(4,5) 383 381 V381EHypochondroplasia¹⁷ 393 391 A391G, Crouzon syndrome¹⁷, Seborrheickeratosis¹⁹ A391E 528 526 M528I⁴³ Proportionate short stature⁴³ 542 540N540S, Hypochondroplasia^(17,18) N540T, N540K 623 621 R623H CATSHLsyndrome⁴⁰ 652 650 K650E, Thanatophoric Dysplasia³, Skeletal K650M,Dysplasia¹⁶, Thanatophoric dysplasia type I¹⁷, K650T, Thanatophoricdysplasia type II¹⁷, Acanthosis K650N, nigricans³², Hypochondroplasia¹⁷K650Q 809 807 X807R, Thanatophoric dysplasia type I¹⁷ (stop) (stop)X807C, X807G, X807S, X807W c.1959 + 19G > Achondroplasia³³ A ^(A)SeeUniParc entry UPI00000534B8 ^(B)See UniParc entry UPI0000001C0F ^(C)SeeUniParc entry UPI000002A99A ^(D)See UniParc entry UPI000012A72A ^(E)SeeUniparc entry UPI0001BE80CD ^(F)See UniParc entry UPI000002A9AC ^(G)SeeUniparc entry UPI000012A72C ^(H)See Uniparc entry UPI000007296F ^(Z)Eachisoform of FGFR1, FGFR2, FGFR3, and FGFR4 has a different length, andthus, the corresponding amino acid position in one isoform of FGFR1,FGFR2, FGFR3, and FGFR4 may be different in another isoform of FGFR1,FGFR2, FGFR3, and FGFR4. The position of each point mutation listedabove in each isoform of FGFR1, FGFR2, FGFR3, and FGFR4 can beidentified by first identifying the isoform(s) of FGFR1, FGFR2, FGFR3,or FGFR4 which correspond to the specific point mutation listed above(by amino acid position and starting amino acid), and then aligning theamino acid sequence of identified isoform(s) of FGFR1, FGFR2, FGFR3, orFGFR4 with the amino acid sequences of the other isoforms of FGFR1,FGFR2, FGFR3, or FGFR4. ¹Yong-Xing et al., Hum. Mol. Genet.9(13):2001-2008, 2000. ²Eeva-Maria Laitinen et al., PLoS One7(6):e39450, 2012. ³Hart et al., Oncogene 19(29):3309-3320, 2000.⁴Shiang et al., Cell 76:335-342, 1994. ⁵Rosseau et al., Nature371:252-254, 1994. ⁶Tavormina et al., Nature Genet. 9:321-328, 1995.⁷Bellus et al., Nature Genet. 10:357-359, 1995. ⁸Muenke et al., NatureGenet. 8:269-274, 1994. ⁹Rutland et al., Nature Genet. 9:173-176, 1995.¹⁰Reardon et al., Nature Genet. 8:98-103, 1994. ¹¹Wilkie et al., NatureGenet. 9:165-172, 1995. ¹²Jabs et al., Nature Genet. 8:275-279, 1994.¹³Japanese Patent No. JP0586899262. ¹⁴Ye et al., Plast. Reconstr. Surg.,137(3):952-61, 2016. ¹⁵U.S. Pat. No. 944709862. ¹⁶Bellus et al., Am. J.Med. Genet. 85(1):53-65, 1999. ¹⁷PCT Patent Application Publication No.WO2016139227A1. ¹⁸Australian Patent Application Publication No.AU2014362227A1. ¹⁹Chinese Patent No. CN102741256B. ²⁰Ohishi et al., Am.J. Med. Genet. A., doi: 10.1002/ajmg.a.37992, 2016. ²¹Nagahara et al.,Clin. Pediatr. Endocrinol., 25(3): 103-106, 2016. ²²Hibberd et al., Am.J. Med. Genet. A., doi: 10.1002/ajmg.a.37862, 2016. ²³Dias et al., Exp.Mol. Pathol., 101(1):116-23, 2016. ²⁴Lin et al., Mol. Med. Rep.,14(3):1941-6, 2016. ²⁵Barnett et al., Hum. Mutat., 37(9):955-63, 2016.²⁶Krstevska-Konstantinova et al., Med. Arch., 70(2):148-50, 2016.²⁷Kuentz et al., Br. J. Dermatol., doi: 10.1111/bjd.14681, 2016. ²⁸Ronet al., Am. J. Case Rep., 15;17:254-8, 2016. ²⁹Fernandes et al., Am. J.Med. Genet. A., 170(6):1532-7, 2016. ³⁰Lindy et al., Am. J. Med. Genet.A., 170(6):1573-9, 2016. ³¹Bennett et al., Am. J. Hum. Genet.,98(3):579-87, 2016. ³²Ichiyama et al., J. Eur. Acad. Dermatol.Venereol., 30(3):442-5, 2016. ³³Zhao et al., Int. J. Clin. Exp. Med.,8(10):19241-9, 2015. ³⁴Hasegawa et al., Am. J. Med. Genet. A.,170A(5):1370-2, 2016. ³⁵Legeai-Mallet, Endocr. Dev., 30:98-105, 2016.³⁶Takagi, Am. J. Med. Genet. A., 167A(11):2851-4, 2015. ³⁷Goncalves,Fertil. Steril., 104(5):1261-7.e1, 2015. ³⁸Miller et al., Journal ofClinical Oncology, 34:Supp. Supplement 15, pp. iii93. Abstract Number:e22500, 2016 Annual Meeting of the American Society of ClinicalOncology, Chicago, IL. ³⁹Sarabipour et al., J. Mol. Biol.,428(20):3903-3910, 2016. ⁴⁰Escobar et al., Am. J. Med. Genet. A.,170(7):1908-11, 2016. ⁴¹Mazen et al., Sex Dev., 10(1):16-22, 2016.⁴²Taylan et al., J Allergy Clin Immunol, 136(2):507-9, 2015. doi:10.1016/j.jaci.2015.02.010 ⁴³Kant et al, Euro Journ Endocrinol,172(6):763-770, 2015. doi: 10.1530/EJE-14-0945 ⁴⁴González-Del Angel etal, Am J med Genet A, 176(1):161-166, 2018. doi: 10.1002/ajmg.a.3852645Lei and Deng, Int J Biol Sci 13(9):1163:1171, 2017. doi:10.7150/ijbs.20792 ⁴⁶Lajeunie et al, Eur J Hum Genet, 14(3):289-298,2006. doi: 10.1038/sj.ejhg.5201558 ⁴⁷Karadimas et al, Prenat Diagn,26(3):258-261, 2006. doi: 10.1002/pd.1392 ⁴⁸Ibrahimi et al, Hum MolGenet 13(19):2313-2324, 2004. doi: 10.1093/hmeddh235 ⁴⁹Trarbach et al, JClin Endocrinol Metab., 91(10):4006-4012, 2006. doi:10.1210/jc.2005-2793 ⁵⁰Dodé et al, Nat Genet, 33(4):463-465, 2003. doi:10.1038/ng1122

Additional point mutations in FGFR1, FGFR2, FGFR3, and FGFR4 have beenidentified to result in resistance of a cancer cell to a FGFR inhibitor.Non-limiting examples of these mutations are depicted in Table BE. Insome embodiments, a FGFR-associated disorder (e.g., any of the cancersdescribed herein) can have one or more of the point mutations listed inTable BE. Also provided herein are methods of treating a subject thatinclude identifying a subject having one or more of the point mutationslisted in Table BE, and administering to the identified subject atherapeutically effective amount of a compound of Formula I (e.g., anyof the exemplary compounds described herein), or a pharmaceuticallyacceptable salt or solvate thereof. Also provided are methods oftreating a subject that include administering to a subject identified ashaving one or more of the point mutations listed in Table BE atherapeutically effective amount of a compound of Formula I (e.g., anyof the exemplary compounds described herein).

TABLE BE FGFR Resistance Mutations Amino acid Amino acid Amino acidposition Non-limiting position (αA1 position (αB1 (other ExemplaryNon-limiting Exemplary FGFR- isoform)^(Z, A) isoform)^(Z, B) isoform)mutations(s) Associated Cancer(s) 546 544 N546K⁵ (In vitro study) 561559 V561M^(3, 5, 7) (In vitro study) 563 561 Y563C⁷ (In vitro study)FGFR2 Amino acid Amino acid Amino acid position Non-limiting position(IIIb position (IIIc (other Exemplary Non-limiting Exemplary FGFR-isoform)^(Z, C) isoform)^(Z, D) isoform) mutation(s) AssociatedCancer(s) 288 288 I288S¹¹ (tumor induced in mice)¹¹ 290 290 W290R¹¹(tumor induced in mice)¹¹ 338 340 Y340C¹¹ (tumor induced in mice)¹¹ 344346 N346K¹¹ (tumor induced in mice)¹¹ 536 535 M536I¹ (In vitro study)538 537 M538I¹ (In vitro study) 548 547 I548V¹ (In vitro study) 549 548I548S¹¹ (tumor induced in mice)¹¹ 549/290 548/290 I548S/W290R¹¹ (tumorinduced in mice)¹¹ 550 549 N550H^(1, 2, 9), (In vitro study),cholangiocarcinoma⁹, N550K¹, (tumor induced in mice)¹¹ N550S¹, N549T¹¹563 562 V562L^(4, 11) (In vitro study), (tumor induced in mice)¹¹ 565564 V565I^(1, 2), (In vitro study), cholangiocarcinoma⁹ V565F^(4, 9) 566565 E566G^(1, 2), (In vitro study), (tumor induced in E565L¹¹ mice)¹¹569 568 S568L¹¹ (tumor induced in mice)¹¹ 569/563 568/562 S568L/V562¹¹(tumor induced in mice)¹¹ 618 617 L618M¹ (In vitro study) 642 641K642N¹, (In vitro study), cholangiocarcinoma⁹, K641R^(9, 11) (tumorinduced in mice)¹¹ 660 659 K660E¹, (In vitro study), (tumor induced inK660M^(2, 11), mice)¹¹ K660N² 719 718 E719G¹ (In vitro study) 770Y770lfsX14¹ (In vitro study) FGFR3 Amino acid Amino acid Amino acidposition Non-limiting position (IIIb position (IIIc (other ExemplaryNon-limiting Exemplary FGFR- isoform)^(Z, E) isoform)^(Z, F) isoform)mutation(s) Associated Cancer(s) 542 540 N540K⁹, (In vitrostudy)^(9, 10) N540D¹⁰ 557 555 V555M^(6, 9), (KMS-11 myeloma cell linederivative), V555L⁹ (in vitro study)⁹ 610 608 L608V⁹ (In vitro study)⁹652 650 K650E⁹ (In vitro study)⁹ FGFR4 Amino acid Amino acid Amino acidposition Non-limiting position position (other Exemplary Non-limitingExemplary FGFR- (P22455-1)^(Z, G) (P22455-2)^(Z, H) isoform) mutation(s)Associated Cancer(s) 388 G388R⁸ Breast cancer ^(A)See UniParc entryUPI00000534B8 ^(B)See UniParc entry UPI0000001C0F ^(C)See UniParc entryUPI000002A99A ^(D)See UniParc entry UPI000012A72A ^(E)See UniParc entryUPI000002A9AC ^(F)See Uniparc entry UPI000012A72C ^(G)See Uniparc entryUPI000012A72D ^(H)See Uniparc entry UPI000013E0B8 ^(Z)Each isoform ofFGFR1, FGFR2, FGFR3, and FGFR4 has a different length, and thus, thecorresponding amino acid position in one isoform of FGFR1, FGFR2, FGFR3,and FGFR4 may be different in another isoform of FGFR1, FGFR2, FGFR3,and FGFR4. The position of each point mutation listed above in eachisoform of FGFR1, FGFR2, FGFR3, and FGFR4 can be identified by firstidentifying the isoform(s) of FGFR1, FGFR2, FGFR3, or FGFR4 whichcorrespond to the specific point mutation listed above (by amino acidposition and starting amino acid), and then aligning the amino acidsequence of identified isoform(s) of FGFR1, FGFR2, FGFR3, or FGFR4 withthe amino acid sequences of the other isoforms of FGFR1, FGFR2, FGFR3,or FGFR4. ¹Byron et al., Neoplasia, 15(8): 975-88, 2013. ²EuropeanPatent Application Publication No. EP3023101A1. ³European Patent No.EP2203449B1. ⁴PCT Application Publication No. WO 2015/099127A1. ⁵Yoza etal., Genes Cells., (10): 1049-1058, 2016. ⁶Chell et al., Oncogene,32(25): 3059-70, 2013. ⁷Bunney et al., EbioMedicine, 2(3): 194-204,2015. ⁸Thussbas et al., J. Clin. Oncol., 24(23): 3747-55, 2006. ⁹Goyalet al, Cancer Discov, 7(3): 252-263, 2017. doi:10.1158/2159-8290.CD-16-1000 ¹⁰Chen et al, Oncogene, 24(56): 8259-8267,2005. doi: 10.1038/sj.onc.1208989 ¹¹Kas et al, Cancer Res, 78(19):5668-5679, 2018. doi: 10.1158/0008-5472.CAN-18-0757

The term “angiogenesis-related disorder” means a disease characterizedin part by an increased number or size of blood vessels in a tissue in asubject or patient, as compared to a similar tissue from a subject nothaving the disease. Non-limiting examples of angiogenesis-relateddisorders include: cancer (e.g., any of the exemplary cancers describedherein, such as prostate cancer, lung cancer, breast cancer, bladdercancer, renal cancer, colon cancer, gastric cancer, pancreatic cancer,ovarian cancer, melanoma, hepatoma, sarcoma, and lymphoma), exudativemacular degeneration, proliferative diabetic retinopathy, ischemicretinopathy, retinopathy of prematurity, neovascular glaucoma, iritisrubeosis, corneal neovascularization, cyclitis, sickle cell retinopathy,and pterygium.

The term “resistant cancer cell to an anti-cancer drug” means a cancercell that demonstrates an increased rate of growth and/or proliferationin the presence of an anti-cancer drug as compared to the rate of growthand/or proliferation of a similar cancer cell (or an average rate ofgrowth and/or proliferation of a population of a similar cancer cells).For example, a cancer cell that demonstrates an increased rate of growthand/or proliferation in the presence of an anti-cancer drug (as comparedto the rate of growth and/or proliferation of a similar cancer cell) canbe present in a patient or a subject (e.g., a patient or a subjecthaving a FGFR-associated cancer).

The term “increasing sensitivity to an anti-cancer drug” means adecrease in the rate of growth and/or proliferation of a resistantcancer cell (to an anti-cancer drug) when contacted with the anti-cancerdrug and at least one of the compounds described herein, as compared tothe rate of growth and/or proliferation of a resistant cancer cell whencontacted with the anti-cancer drug alone. Although many of themechanisms discussed so far are the result of genetic dysregulation ofthe FGF/FGFR signaling axis, ligand-dependent signaling is also likelyto play a key role in cancer development (e.g., described as“Upregulation of Activity” in Table BB). Autocrine FGF overproductionhas been reported in many tumor types (Turner N, Grose R., Nat RevCancer 2010; 10:116-129). In vitro studies have shown that FGF5overexpression has been associated with a number of tumor cell lines(lung, esophagus, melanoma, colon, and prostate; Hanada K, et al.,Cancer Res 2001; 61:5511-5516), and in hepatocellular carcinomas (HCC),the upregulation of FGF2, 8, 17, and 18 initiates autocrine growthstimulation, cell survival, and neoangiogenesis (Uematsu S, et al., JGastroenterol Hepatol 2005; 20:583-588; Hu M C, et al., Mol Cell Biol1998; 18:6063-6074; Kin M, et al., J Hepatol 1997; 27:677-687;Gauglhofer C, et al., Hepatology 2011; 53:854-864). Further, HCC hasbeen found to develop in transgenic mice overexpressing the hormonalFGF19 (Nicholes K, et al., Am J Pathol 2002; 160:2295-2307), and FGF19is found on an amplicon on chromosome 11q that also invariably containsthe adjacent FGF3, FGF4, and Cyclin D1 (CCND1) genes. This amplicon isfound in various diseases, including head and neck squamous cellcarcinoma, breast cancer, and squamous NSCLC. Although there isuncertainty about the key oncogenic gene on this amplicon or apresumption that it is CCND1, genetic knockdown of FGF19 inhibits thegrowth of HCC cell lines carrying the amplicon (Sawey E T, et al.,Cancer Cell 2011; 19:347-358). Autocrine FGF2-FGFR1 feedback loops havealso been reported in NSCLC cell lines and in human melanomas grown assubcutaneous tumors in nude mice (Marek L, et al., Mol Pharmacol 2009;75:196-207; Wang Y, Becker D., Nat Med 1997; 3:887-893).

Paracrine production of FGFs has also been reported in multiple tumortypes. High levels of serum FGF2 have been observed in small cell lungcancer and are associated with a poor prognosis (Ruotsalainen T, et al.,Cancer Epidemiol Biomarkers Prev 2002; 11:1492-1495), possibly becauseof an FGF2-mediated cytoprotective effect, whereby the expression ofantiapoptotic proteins are upregulated, promoting resistance to currentanticancer treatments (Pardo O E, et al., EMBO J 2006; 25:3078-3088).Increased paracrine expression of one or more of FGF1, 2, 4, 5, 8, and18 has been found to promote tumor neoangiogenesis in preclinical modelsvia the main endothelial FGFRs, FGFR1 and 2 (Presta M, et al., CytokineGrowth Factor Rev 2005; 16:159-178). Poor prognosis has been associatedwith neoangiogenesis in ovarian cancer and melanomas (Birrer M J, etal., J Clin Oncol 2007; 25:2281-2287).

In addition to overexpression of FGFs, altered splicing of FGFR mRNAs isanother mechanism by which ligand-dependent signaling is upregulated.Altered FGFR mRNA splicing can allow tumor cells to be stimulated by abroader range of FGFs than would be capable under normal physiologicconditions (Zhang X, et al., J Biol Chem 2006; 281:15694-15700). Alteredsplicing of the IgIII domains in FGFRs 1,2, and 3 can switch receptorbinding affinity in cancer cells towards FGFs found in the healthystroma, creating an aberrant paracrine signaling loop (Wesche J, HaglundK, Haugsten E M. et al., Biochem J 2011; 437:199-213). In bladder andprostate cancer cell lines, a switch from the FGFR2-IIIb isoform to theIIIc isoform has been associated with tumor progression,epithelial-mesenchymal transition, and increased invasiveness (Wesche J,et al., Biochem J 2011; 437:199-213).

Accordingly, provided herein are methods for treating a subjectdiagnosed with (or identified as having) a FGFR-associated disease ordisorder (e.g., a FGFR-associated cancer) that include administering tothe subject a therapeutically effective amount of a compound of FormulaI or a pharmaceutically acceptable salt or solvate thereof. Alsoprovided herein are methods for treating a subject identified ordiagnosed as having a FGFR-associated disease or disorder (e.g., aFGFR-associated cancer) that include administering to the subject atherapeutically effective amount of a compound of Formula I orpharmaceutically acceptable salt or solvate thereof. In someembodiments, the subject that has been identified or diagnosed as havinga FGFR-associated disease or disorder (e.g., a FGFR-associated cancer)through the use of a regulatory agency-approved, e.g., FDA-approved testor assay for identifying dysregulation of a FGFR gene, a FGFR kinase, orexpression or activity or level of any of the same, in a subject or abiopsy sample from the subject or by performing any of the non-limitingexamples of assays described herein. In some embodiments, the test orassay is provided as a kit. In some embodiments, the FGFR-associateddisease or disorder is a FGFR-associated cancer. For example, theFGFR-associated cancer can be a cancer that includes one or more FGFRinhibitor resistance mutations.

Also provided are methods for treating a disease or disorder in asubject in need thereof, the method comprising: (a) detecting aFGFR-associated disease or disorder in the subject; and (b)administering to the subject a therapeutically effective amount of acompound of Formula I or pharmaceutically acceptable salt or solvatethereof. Some embodiments of these methods further include administeringto the subject an additional therapy or therapeutic agent (e.g., asecond FGFR inhibitor, a second compound of Formula I or apharmaceutically acceptable salt or solvate thereof, or animmunotherapy. In some embodiments, the subject was previously treatedwith a first FGFR inhibitor or previously treated with anothertreatment. In some embodiments, the subject is determined to have aFGFR-associated disease or disorder through the use of a regulatoryagency-approved, e.g., FDA-approved test or assay for identifyingdysregulation of a FGFR gene, a FGFR kinase, or expression or activityor level of any of the same, in a subject or a biopsy sample from thesubject or by performing any of the non-limiting examples of assaysdescribed herein. In some embodiments, the test or assay is provided asa kit.

Also provided are methods for treating cancer in a subject in needthereof, the method comprising: (a) detecting a FGFR-associated cancerin the subject; and (b) administering to the subject a therapeuticallyeffective amount of a compound of Formula I or pharmaceuticallyacceptable salt or solvate thereof. Some embodiments of these methodsfurther include administering to the subject an additional therapy ortherapeutic agent (e.g., a second FGFR inhibitor, a second compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof, oran immunotherapy). In some embodiments, the subject was previouslytreated with a first FGFR inhibitor or previously treated with anotheranticancer treatment, e.g., at least partial resection of the tumor orradiation therapy. In some embodiments, the subject is determined tohave a FGFR-associated cancer through the use of a regulatoryagency-approved, e.g., FDA-approved test or assay for identifyingdysregulation of a FGFR gene, a FGFR kinase, or expression or activityor level of any of the same, in a subject or a biopsy sample from thesubject or by performing any of the non-limiting examples of assaysdescribed herein. In some embodiments, the test or assay is provided asa kit. In some embodiments, the cancer is a FGFR-associated cancer. Forexample, the FGFR-associated cancer can be a cancer that includes one ormore FGFR inhibitor resistance mutations.

Also provided are methods of treating a subject that include performingan assay on a sample obtained from the subject to determine whether thesubject has a dysregulation of a FGFR gene, a FGFR kinase, or expressionor activity or level of any of the same, and administering (e.g.,specifically or selectively administering) a therapeutically effectiveamount of a compound of Formula I or pharmaceutically acceptable salt orsolvate thereof to the subject determined to have a dysregulation of aFGFR gene, a FGFR kinase, or expression or activity or level of any ofthe same. Some embodiments of these methods further includeadministering to the subject an additional therapy or therapeutic agent(e.g., a second FGFR inhibitor, a second compound of Formula I or apharmaceutically acceptable salt or solvate thereof, or immunotherapy).In some embodiments of these methods, the subject was previously treatedwith a first FGFR inhibitor or previously treated with anotheranticancer treatment, e.g., at least partial resection of a tumor orradiation therapy. In some embodiments, the subject is a subjectsuspected of having a FGFR-associated disease or disorder (e.g., aFGFR-associated cancer), a subject presenting with one or more symptomsof a FGFR-associated disease or disorder (e.g., a FGFR-associatedcancer), or a subject having an elevated risk of developing aFGFR-associated disease or disorder (e.g., a FGFR-associated cancer). Insome embodiments, the assay utilizes next generation sequencing,pyrosequencing, immunohistochemistry, or break apart FISH analysis. Insome embodiments, the assay is a regulatory agency-approved assay, e.g.,FDA-approved kit. In some embodiments, the assay is a liquid biopsy.Additional, non-limiting assays that may be used in these methods aredescribed herein. Additional assays are also known in the art. In someembodiments, the dysregulation of a FGFR gene, a FGFR kinase, orexpression or activity or level of any of the same includes one or moreFGFR inhibitor resistance mutations.

Also provided is a compound of Formula I or pharmaceutically acceptablesalt or solvate thereof for use in treating a FGFR-associated disease ordisorder (e.g., a FGFR-associated cancer) in a subject identified ordiagnosed as having a FGFR-associated disease or disorder (e.g., aFGFR-associated cancer) through a step of performing an assay (e.g., anin vitro assay) on a sample obtained from the subject to determinewhether the subject has a dysregulation of a FGFR gene, a FGFR kinase,or expression or activity or level of any of the same, where thepresence of a dysregulation of a FGFR gene, a FGFR kinase, or expressionor activity or level of any of the same, identifies that the subject hasa FGFR-associated disease or disorder (e.g., a FGFR-associated cancer).Also provided is the use of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof for the manufactureof a medicament for treating a FGFR-associated disease or disorder(e.g., a FGFR-associated cancer) in a subject identified or diagnosed ashaving a FGFR-associated disease or disorder (e.g., a FGFR-associatedcancer) through a step of performing an assay on a sample obtained fromthe subject to determine whether the subject has a dysregulation of aFGFR gene, a FGFR kinase, or expression or activity or level of any ofthe same where the presence of dysregulation of a FGFR gene, a FGFRkinase, or expression or activity or level of any of the same,identifies that the subject has a FGFR-associated disease or disorder(e.g., a FGFR-associated cancer). Some embodiments of any of the methodsor uses described herein further include recording in the subject'sclinical record (e.g., a computer readable medium) that the subject isdetermined to have a dysregulation of a FGFR gene, a FGFR kinase, orexpression or activity or level of any of the same, through theperformance of the assay, should be administered a compound of Formula Ior pharmaceutically acceptable salt or solvate thereof. In someembodiments, the assay utilizes next generation sequencing,pyrosequencing, immunohistochemistry, or break apart FISH analysis. Insome embodiments, the assay is a regulatory agency-approved assay, e.g.,FDA-approved kit. In some embodiments, the assay is a liquid biopsy. Insome embodiments, the dysregulation of a FGFR gene, a FGFR kinase, orexpression or activity or level of any of the same includes one or moreFGFR inhibitor resistance mutations.

Also provided is a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof, for use in the treatment of adisease or disorder in a subject in need thereof or a subject identifiedor diagnosed as having a FGFR-associated disease or disorder. Alsoprovided is the use of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof for the manufacture of a medicamentfor treating a disease or disorder in a subject identified or diagnosedas having a FGFR-associated disease or disorder. In some embodiments,the cancer is a FGFR-associated cancer, for example, a FGFR-associatedcancer having one or more FGFR inhibitor resistance mutations. In someembodiments, a subject is identified or diagnosed as having aFGFR-associated disease or disorder through the use of a regulatoryagency-approved, e.g., FDA-approved, kit for identifying dysregulationof a FGFR gene, a FGFR kinase, or expression or activity or level of anyof the same, in a subject or a biopsy sample from the sample. Asprovided herein, a FGFR-associated disease or disorder includes thosedescribed herein and known in the art.

Also provided is a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof, for use in the treatment of a cancerin a subject in need thereof or a subject identified or diagnosed ashaving a FGFR-associated cancer. Also provided is the use of a compoundof Formula I or a pharmaceutically acceptable salt or solvate thereoffor the manufacture of a medicament for treating a cancer in a subjectidentified or diagnosed as having a FGFR-associated cancer. In someembodiments, the cancer is a FGFR-associated cancer, for example, aFGFR-associated cancer having one or more FGFR inhibitor resistancemutations. In some embodiments, a subject is identified or diagnosed ashaving a FGFR-associated cancer through the use of a regulatoryagency-approved, e.g., FDA-approved, kit for identifying dysregulationof a FGFR gene, a FGFR kinase, or expression or activity or level of anyof the same, in a subject or a biopsy sample from the sample. Asprovided herein, a FGFR-associated cancer includes those describedherein and known in the art.

In some embodiments of any of the methods or uses described herein, thesubject has been identified or diagnosed as having a cancer with adysregulation of a FGFR gene, a FGFR kinase, or expression or activityor level of any of the same. In some embodiments of any of the methodsor uses described herein, the subject has a tumor that is positive for adysregulation of a FGFR gene, a FGFR kinase, or expression or activityor level of any of the same. In some embodiments of any of the methodsor uses described herein, the subject can be a subject with a tumor(s)that is positive for a dysregulation of a FGFR gene, a FGFR kinase, orexpression or activity or level of any of the same. In some embodimentsof any of the methods or uses described herein, the subject can be asubject whose tumors have a dysregulation of a FGFR gene, a FGFR kinase,or expression or activity or level of any of the same. In someembodiments of any of the methods or uses described herein, the subjectis suspected of having a FGFR-associated cancer (e.g., a cancer havingone or more FGFR inhibitor resistance mutations). In some embodiments,provided herein are methods for treating a FGFR-associated cancer in asubject in need of such treatment, the method comprising a) detecting adysregulation of a FGFR gene, a FGFR kinase, or the expression oractivity or level of any of the same in a sample from the subject; andb) administering a therapeutically effective amount of a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the dysregulation of a FGFR gene, a FGFR kinase, orthe expression or activity or level of any of the same includes one ormore fusion proteins. In some embodiments of any of the methods or usesdescribed herein, the subject is suspected of having a FGFR-associatedcancer (e.g., a cancer having one or more FGFR inhibitor resistancemutations). Non-limiting examples of FGFR gene fusion proteins aredescribed in Table BA. In some embodiments, the fusion protein isFGFR3-TACC3. In some embodiments, the dysregulation of a FGFR gene, aFGFR kinase, or the expression or activity or level of any of the sameincludes one or more FGFR kinase protein pointmutations/insertions/deletions. Non-limiting examples of FGFR kinaseprotein point mutations/insertions/deletions are described in Table BC.In some embodiments, the FGFR kinase protein pointmutations/insertions/deletions are selected from the group consisting ofpoint mutations/insertions/deletions corresponding to V561M in SEQ IDNO. 1, V564I or V564F in SEQ ID NO. 3, or V555M in SEQ ID NO. 5. In someembodiments, the dysregulation of a FGFR gene, a FGFR kinase, or theexpression or activity or level of any of the same includes one or moreFGFR inhibitor resistance mutations. Non-limiting examples of FGFRinhibitor resistance mutations are described in Table BE. In someembodiments, the FGFR inhibitor resistance mutation corresponds to V561Min SEQ ID NO. 1, V564I or V564F in SEQ ID NO. 3, or V555M in SEQ ID NO.5. In some embodiments, the cancer with a dysregulation of a FGFR gene,a FGFR kinase, or expression or activity or level of any of the same isdetermined using a regulatory agency-approved, e.g., FDA-approved, assayor kit. In some embodiments, the tumor that is positive for adysregulation of a FGFR gene, a FGFR kinase, or expression or activityor level of any of the same is a tumor positive for one or more FGFRinhibitor resistance mutations. In some embodiments, the tumor with adysregulation of a FGFR gene, a FGFR kinase, or expression or activityor level of any of the same is determined using a regulatoryagency-approved, e.g., FDA-approved, assay or kit.

In some embodiments of any of the methods or uses described herein, thesubject has a clinical record indicating that the subject has a tumorthat has a dysregulation of a FGFR gene, a FGFR kinase, or expression oractivity or level of any of the same (e.g., a tumor having one or moreFGFR inhibitor resistance mutations). In some embodiments, the clinicalrecord indicates that the subject should be treated with one or more ofthe compounds of Formula I or a pharmaceutically acceptable salts orsolvates thereof or compositions provided herein. In some embodiments,the cancer with a dysregulation of a FGFR gene, a FGFR kinase, orexpression or activity or level of any of the same is a cancer havingone or more FGFR inhibitor resistance mutations. In some embodiments,the cancer with a dysregulation of a FGFR gene, a FGFR kinase, orexpression or activity or level of any of the same is determined using aregulatory agency-approved, e.g., FDA-approved, assay or kit. In someembodiments, the tumor that is positive for a dysregulation of a FGFRgene, a FGFR kinase, or expression or activity or level of any of thesame is a tumor positive for one or more FGFR inhibitor resistancemutations. In some embodiments, the tumor with a dysregulation of a FGFRgene, a FGFR kinase, or expression or activity or level of any of thesame is determined using a regulatory agency-approved, e.g.,FDA-approved, assay or kit.

Also provided are methods of treating a subject that includeadministering a therapeutically effective amount of a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof to asubject having a clinical record that indicates that the subject has adysregulation of a FGFR gene, a FGFR kinase, or expression or activityor level of any of the same. Also provided is the use of a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof forthe manufacture of a medicament for treating a FGFR-associated cancer ina subject having a clinical record that indicates that the subject has adysregulation of a FGFR gene, a FGFR kinase, or expression or activityor level of any of the same. Some embodiments of these methods and usescan further include: a step of performing an assay (e.g., an in vitroassay) on a sample obtained from the subject to determine whether thesubject has a dysregulation of a FGFR gene, a FGFR kinase, or expressionor activity or level of any of the same, and recording the informationin a subject's clinical file (e.g., a computer readable medium) that thesubject has been identified to have a dysregulation of a FGFR gene, aFGFR kinase, or expression or activity or level of any of the same. Insome embodiments, the assay is an in vitro assay. For example, an assaythat utilizes next generation sequencing, immunohistochemistry, or breakapart FISH analysis. In some embodiments, the assay is a regulatoryagency-approved, e.g., FDA-approved, kit. In some embodiments, the assayis a liquid biopsy. In some embodiments, the dysregulation of a FGFRgene, FGFR kinase, or expression or activity or level of any of the sameincludes one or more FGFR inhibitor resistance mutations.

Also provided herein is a method of treating a subject. In someembodiments, the method includes performing an assay on a sampleobtained from the subject to determine whether the subject has adysregulation of a FGFR gene, a FGFR protein, or expression or level ofany of the same. In some such embodiments, the method also includesadministering to a subject determined to have a dysregulation of a FGFRgene, a FGFR protein, or expression or activity, or level of any of thesame a therapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the method includes determining that a subject has adysregulation of a FGFR gene, a FGFR protein, or expression or level ofany of the same via an assay performed on a sample obtained from thesubject. In some such embodiments, the method also includesadministering to a subject a therapeutically effective amount of acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof. In some embodiments, the dysregulation in a FGFR gene, a FGFRkinase protein, or expression or activity of the same is a gene orchromosome translocation that results in the expression of a FGFR fusionprotein (e.g., any of the FGFR fusion proteins described herein). Insome embodiments, the FGFR fusion can be selected from a FGFR3-TACC3fusion and a FGFR2-BICC1 fusion. In some embodiments, the dysregulationin a FGFR gene, a FGFR kinase protein, or expression or activity orlevel of any of the same is one or more point mutation in the FGFR gene(e.g., any of the one or more of the FGFR point mutations describedherein). The one or more point mutations in a FGFR gene can result,e.g., in the translation of a FGFR protein having an amino acidsubstitution that corresponds to one or more of the following: V561M inSEQ ID NO. 1, V564I or V564F in SEQ ID NO. 3, or V555M in SEQ ID NO. 5.In some embodiments, the dysregulation in a FGFR gene, a FGFR kinaseprotein, or expression or activity or level of any of the same is one ormore FGFR inhibitor resistance mutations (e.g., any combination of theone or more FGFR inhibitor resistance mutations described herein). Someembodiments of these methods further include administering to thesubject an additional therapy or therapeutic agent (e.g., a second FGFRinhibitor, a second compound of Formula I, or immunotherapy).

In some embodiments, the compounds provided herein exhibit brain and/orcentral nervous system (CNS) penetrance. Such compounds are capable ofcrossing the blood brain barrier and inhibiting a FGFR kinase in thebrain and/or other CNS structures. In some embodiments, the compoundsprovided herein are capable of crossing the blood brain barrier in atherapeutically effective amount. For example, treatment of a subjectwith cancer (e.g., a FGFR-associated cancer such as a FGFR-associatedbrain or CNS cancer) can include administration (e.g., oraladministration) of the compound to the subject. In some suchembodiments, the compounds provided herein (e.g., compounds of Formula)are useful for treating a primary brain tumor or metastatic brain tumor.For example, the compounds can be used in the treatment of one or moreof gliomas such as glioblastoma (also known as glioblastoma multiforme),astrocytomas, oligodendrogliomas, ependymomas, and mixed gliomas,meningiomas, medulloblastomas, gangliogliomas, schwannomas(neurilemmomas), and craniopharyngiomas (see, for example, the tumorslisted in Louis, D. N. et al. Acta Neuropathol 131(6), 803-820 (June2016)). In some embodiments, the brain tumor is a primary brain tumor.In some embodiments, the subject has previously been treated withanother anticancer agent, e.g., another FGFR inhibitor (e.g., a compoundthat is not a compound of Formula I) or a multi-kinase inhibitor. Insome embodiments, the brain tumor is a metastatic brain tumor. In someembodiments, the subject has previously been treated with anotheranticancer agent, e.g., another FGFR inhibitor (e.g., a compound that isnot a compound of Formula I) or a multi-kinase inhibitor.

Also provided are methods (e.g., in vitro methods) of selecting atreatment for a subject identified or diagnosed as having aFGFR-associated cancer. Some embodiments can further includeadministering the selected treatment to the subject identified ordiagnosed as having a FGFR-associated cancer. For example, the selectedtreatment can include administration of a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof. Some embodiments can further include a step ofperforming an assay on a sample obtained from the subject to determinewhether the subject has a dysregulation of a FGFR gene, a FGFR kinase,or expression or activity or level of any of the same, and identifyingand diagnosing a subject determined to have a dysregulation of a FGFRgene, a FGFR kinase, or expression or activity or level of any of thesame, as having a FGFR-associated cancer. In some embodiments, thecancer is a FGFR-associated cancer having one or more FGFR inhibitorresistance mutations. In some embodiments, the subject has beenidentified or diagnosed as having a FGFR-associated cancer through theuse of a regulatory agency-approved, e.g., FDA-approved, kit foridentifying dysregulation of a FGFR gene, a FGFR kinase, or expressionor activity or level of any of the same, in a subject or a biopsy samplefrom the subject. In some embodiments, the FGFR-associated cancers is acancer described herein or known in the art. In some embodiments, theassay is an in vitro assay. For example, an assay that utilizes the nextgeneration sequencing, immunohistochemistry, or break apart FISHanalysis. In some embodiments, the assay is a regulatoryagency-approved, e.g., FDA-approved, kit. In some embodiments, the assayis a liquid biopsy.

Also provided herein are methods of selecting a treatment for a subject,wherein the methods include a step of performing an assay on a sampleobtained from the subject to determine whether the subject has adysregulation of a FGFR gene, a FGFR kinase, or expression or activityor level of any of the same (e.g., one or more FGFR inhibitor resistancemutations), and identifying or diagnosing a subject determined to have adysregulation of a FGFR gene, a FGFR kinase, or expression or activityor level of any of the same, as having a FGFR-associated cancer. Someembodiments further include administering the selected treatment to thesubject identified or diagnosed as having a FGFR-associated cancer. Forexample, in some embodiments, the selected treatment can includeadministration of a therapeutically effective amount of a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof tothe subject identified or diagnosed as having a FGFR-associated cancer.In some embodiments, the assay is an in vitro assay. For example, anassay that utilizes the next generation sequencing,immunohistochemistry, or break apart FISH analysis. In some embodiments,the assay is a regulatory agency-approved, e.g., FDA-approved, kit. Insome embodiments, the assay is a liquid biopsy.

Also provided are methods of selecting a subject for treatment, whereinthe methods include selecting, identifying, or diagnosing a subjecthaving a FGFR-associated cancer, and selecting the subject for treatmentincluding administration of a therapeutically effective amount of acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof. In some embodiments, identifying or diagnosing a subject ashaving a FGFR-associated cancer can include a step of performing anassay on a sample obtained from the subject to determine whether thesubject has a dysregulation of a FGFR gene, a FGFR kinase, or expressionor activity or level of any of the same, and identifying or diagnosing asubject determined to have a dysregulation of a FGFR gene, a FGFRkinase, or expression or activity or level of any of the same, as havinga FGFR-associated cancer. In some embodiments, the method of selecting asubject for treatment can be used as a part of a clinical study thatincludes administration of various treatments of a FGFR-associatedcancer. In some embodiments, a FGFR-associated cancer is a cancer havingone or more FGFR inhibitor resistance mutations. In some embodiments,the assay is an in vitro assay. For example, an assay that utilizes thenext generation sequencing, immunohistochemistry, or break apart FISHanalysis. In some embodiments, the assay is a regulatoryagency-approved, e.g., FDA-approved, kit. In some embodiments, the assayis a liquid biopsy. In some embodiments, the dysregulation of the FGFRgene, the FGFR kinase, or expression or activity or level of any of thesame includes one or more FGFR inhibitor resistance mutations.

In some embodiments of any of the methods or uses described herein, anassay used to determine whether the subject has a dysregulation of aFGFR gene, or a FGFR kinase, or expression or activity or level of anyof the same, using a sample from a subject can include, for example,next generation sequencing, immunohistochemistry, fluorescencemicroscopy, break apart FISH analysis, Southern blotting, Westernblotting, FACS analysis, Northern blotting, and PCR-based amplification(e.g., RT-PCR and quantitative real-time RT-PCR). As is well-known inthe art, the assays are typically performed, e.g., with at least onelabelled nucleic acid probe or at least one labelled antibody orantigen-binding fragment thereof. Assays can utilize other detectionmethods known in the art for detecting dysregulation of a FGFR gene, aFGFR kinase, or expression or activity or levels of any of the same(see, e.g., the references cited herein). In some embodiments, thedysregulation of the FGFR gene, the FGFR kinase, or expression oractivity or level of any of the same includes one or more FGFR inhibitorresistance mutations. In some embodiments, the sample is a biologicalsample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) fromthe subject. In some embodiments, the subject is a subject suspected ofhaving a FGFR-associated cancer, a subject having one or more symptomsof a FGFR-associated cancer, and/or a subject that has an increased riskof developing a FGFR-associated cancer).

Exemplary assays for detecting dysregulation of a FGFR gene, a FGFRprotein, or expression or activity, or levels of the same arecommercially available, e.g., FGFR Pathway Mutation PCR Array (Qiagen),HTG Edge FGFR Expression Assay (HTG Molecular Diagnostics), HTScan® FGFReceptor 1 Kinase Assay Kit (Cell Signaling Technology), Vysis LSIIGH/FGFR3 Dual Color, Dual Fusion Translocation Probe (AbbottMolecular), FGFR1 FISH Probe (Empire Genomics), FGFR1 FISH (SonicGenomics), FISH IGH/FGFR3 (Quest Diagnostics), FGFR1 (8p11) [RUO] (LeicaBiosystems), FGFR1 Break Apart FISH Probe (Empire Genomics),FGFR2/CEN10p FISH Probe (Abnova Corporation), FGFR2 (10q26) [ASR] (LeicaBiosystems), Anti-FGFR-4 (IN), Z-FISH (AnaSpec), ZytoLight® SPEC FGFR2Break Apart Probe (Bio-Optica), FGFR3 (4p16.3) (ZytoVision), andZytoLight® SPEC FGFR3/CEN4 Dual Color Probe (ZytoVision). Additionalassays for detecting dysregulation of a FGFR gene, a FGFR protein, orexpression or activity or levels of the same are known in the art.

In some embodiments, dysregulation of a FGFR gene, a FGFR kinase, or theexpression or activity or level of any of the same can be identifiedusing a liquid biopsy (variously referred to as a fluid biopsy or fluidphase biopsy). See, e.g., Karachialiou et al., “Real-time liquidbiopsies become a reality in cancer treatment”, Ann. Transl. Med.,3(3):36,2016. Liquid biopsy methods can be used to detect total tumorburden and/or the dysregulation of a FGFR gene, a FGFR kinase, or theexpression or activity or level of any of the same. Liquid biopsies canbe performed on biological samples obtained relatively easily from asubject (e.g., via a simple blood draw) and are generally less invasivethan traditional methods used to detect tumor burden and/ordysregulation of a FGFR gene, a FGFR kinase, or the expression oractivity or level of any of the same. In some embodiments, liquidbiopsies can be used to detect the presence of dysregulation of a FGFRgene, a FGFR kinase, or the expression or activity or level of any ofthe same at an earlier stage than traditional methods. In someembodiments, the biological sample to be used in a liquid biopsy caninclude, blood, plasma, urine, cerebrospinal fluid, saliva, sputum,broncho-alveolar lavage, bile, lymphatic fluid, cyst fluid, stool,ascites, and combinations thereof. In some embodiments, a liquid biopsycan be used to detect circulating tumor cells (CTCs). In someembodiments, a liquid biopsy can be used to detect circulating free DNA(cfDNA). In some embodiments, circulating free DNA detected using aliquid biopsy is circulating tumor DNA (ctDNA) that is derived fromtumor cells. Analysis of ctDNA (e.g., using sensitive detectiontechniques such as, without limitation, next-generation sequencing(NGS), traditional PCR, digital PCR, or microarray analysis) can be usedto identify dysregulation of a FGFR gene, a FGFR kinase, or theexpression or activity or level of any of the same.

In some embodiments, ctDNA derived from a single gene can be detectedusing a liquid biopsy. In some embodiments, ctDNA derived from aplurality of genes (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30,35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more, or anynumber of genes in between these numbers) can be detected using a liquidbiopsy. In some embodiments, ctDNA derived from a plurality of genes canbe detected using any of a variety of commercially-available testingpanels (e.g., commercially-available testing panels designed to detectdysregulation of a FGFR gene, a FGFR kinase, or the expression oractivity or level of any of the same). Liquid biopsies can be used todetect dysregulation of a FGFR gene, a FGFR kinase, or the expression oractivity or level of any of the same including, without limitation,point mutations or single nucleotide variants (SNVs), copy numbervariants (CNVs), genetic fusions (e.g., translocations orrearrangements), insertions, deletions, or any combination thereof. Insome embodiments, a liquid biopsy can be used to detect a germlinemutation. In some embodiments, a liquid biopsy can be used to detect asomatic mutation. In some embodiments, a liquid biopsy can be used todetect a primary genetic mutation (e.g., a primary mutation or a primaryfusion that is associated with initial development of a disease, e.g.,cancer). In some embodiments, a liquid biopsy can be used to detect agenetic mutation that develops after development of the primary geneticmutation (e.g., a resistance mutation that arises in response to atreatment administered to a subject). In some embodiments, adysregulation of a FGFR gene, a FGFR kinase, or the expression oractivity or level of any of the same identified using a liquid biopsy isalso present in a cancer cell that is present in the subject (e.g., in atumor). In some embodiments, any of the types of dysregulation of a FGFRgene, a FGFR kinase, or the expression or activity or level of any ofthe same described herein can be detected using a liquid biopsy. In someembodiments, a genetic mutation identified via a liquid biopsy can beused to identify the subject as a candidate for a particular treatment.For example, detection of dysregulation of a FGFR gene, a FGFR kinase,or the expression or activity or level of any of the same in the subjectcan indicate that the subject will be responsive to a treatment thatincludes administration of a compound of Formula I or a pharmaceuticallyacceptable salt thereof.

Liquid biopsies can be performed at multiple times during a course ofdiagnosis, a course of monitoring, and/or a course of treatment todetermine one or more clinically relevant parameters including, withoutlimitation, progression of the disease, efficacy of a treatment, ordevelopment of resistance mutations after administering a treatment tothe subject. For example, a first liquid biopsy can be performed at afirst time point and a second liquid biopsy can be performed at a secondtime point during a course of diagnosis, a course of monitoring, and/ora course of treatment. In some embodiments, the first time point can bea time point prior to diagnosing a subject with a disease (e.g., whenthe subject is healthy), and the second time point can be a time pointafter subject has developed the disease (e.g., the second time point canbe used to diagnose the subject with the disease). In some embodiments,the first time point can be a time point prior to diagnosing a subjectwith a disease (e.g., when the subject is healthy), after which thesubject is monitored, and the second time point can be a time pointafter monitoring the subject. In some embodiments, the first time pointcan be a time point after diagnosing a subject with a disease, afterwhich a treatment is administered to the subject, and the second timepoint can be a time point after the treatment is administered; in suchcases, the second time point can be used to assess the efficacy of thetreatment (e.g., if the genetic mutation(s) detected at the first timepoint are reduced in abundance or are undetectable) or to determine thepresence of a resistance mutation that has arisen as a result of thetreatment. In some embodiments, a treatment to be administered to asubject can include a compound of Formula I or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the efficacy of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof, can be determinedby assessing the allele frequency of a dysregulation of a FGFR gene incfDNA obtained from a subject at different time points, e.g., cfDNAobtained from the subject at a first time point and cfDNA obtained fromthe subject at a second time point, where at least one dose of acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof is administered to the subject between the first and second timepoints. Some embodiments of these methods can further includeadministering to the subject the at least one dose of the compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof,between the first and second time points. For example, a reduction(e.g., a 1% to about a 99% reduction, a 1% to about a 95% reduction, a1% to about a 90% reduction, a 1% to about a 85% reduction, a 1% toabout a 80% reduction, a 1% to about a 75% reduction, a 1% reduction toabout a 70% reduction, a 1% reduction to about a 65% reduction, a 1%reduction to about a 60% reduction, a 1% reduction to about a 55%reduction, a 1% reduction to about a 50% reduction, a 1% reduction toabout a 45% reduction, a 1% reduction to about a 40% reduction, a 1%reduction to about a 35% reduction, a 1% reduction to about a 30%reduction, a 1% reduction to about a 25% reduction, a 1% reduction toabout a 20% reduction, a 1% reduction to about a 15% reduction, a 1%reduction to about a 10% reduction, a 1% to about a 5% reduction, abouta 5% to about a 99% reduction, about a 10% to about a 99% reduction,about a 15% to about a 99% reduction, about a 20% to about a 99%reduction, about a 25% to about a 99% reduction, about a 30% to about a99% reduction, about a 35% to about a 99% reduction, about a 40% toabout a 99% reduction, about a 45% to about a 99% reduction, about a 50%to about a 99% reduction, about a 55% to about a 99% reduction, about a60% to about a 99% reduction, about a 65% to about a 99% reduction,about a 70% to about a 99% reduction, about a 75% to about a 95%reduction, about a 80% to about a 99% reduction, about a 90% reductionto about a 99% reduction, about a 95% to about a 99% reduction, about a5% to about a 10% reduction, about a 5% to about a 25% reduction, abouta 10% to about a 30% reduction, about a 20% to about a 40% reduction,about a 25% to about a 50% reduction, about a 35% to about a 55%reduction, about a 40% to about a 60% reduction, about a 50% reductionto about a 75% reduction, about a 60% reduction to about 80% reduction,or about a 65% to about a 85% reduction) in the allele frequency (AF) ofthe dysregulation of a FGFR gene in the cfDNA obtained from the subjectat the second time point as compared to the allele frequency (AF) of thedysregulation of a FGFR gene in the cfDNA obtained from the subject atthe first time point indicates that the treatment (e.g., a compound ofFormula I or a pharmaceutically acceptable salt thereof), was effectivein the subject. In some embodiments, the AF is reduced such that thelevel is below the detection limit of the instrument. Alternatively, anincrease in the allele frequency (AF) of the dysregulation of a FGFRgene in the cfDNA obtained from the subject at the second time point ascompared to the allele frequency (AF) of the dysregulation of a FGFRgene in the cfDNA obtained from the subject at the first time pointindicates that the treatment (e.g., a compound of Formula I or apharmaceutically acceptable salt thereof) was not effective in thesubject (e.g., the subject has developed a resistance mutation to thetreatment (e.g., a compound of Formula I or a pharmaceuticallyacceptable salt thereof). Some embodiments of these methods can furtherinclude, administering additional doses of a compound of Formula I or apharmaceutically acceptable salt thereof, to a subject in which acompound of Formula I or a pharmaceutically acceptable salt thereof, wasdetermined to be effective. Some embodiments of these methods canfurther include, administering a different treatment (e.g., a treatmentthat does not include the administration of compound of Formula I or apharmaceutically acceptable salt thereof, as a monotherapy) to a subjectin which a compound of Formula I or a pharmaceutically acceptable saltthereof, was determined not to be effective.

In some examples of these methods, the time difference between the firstand second time points can be about 1 day to about 1 year, about 1 dayto about 11 months, about 1 day to about 10 months, about 1 day to about9 months, about 1 day to about 8 months, about 1 day to about 7 months,about 1 day to about 6 months, about 1 day to about 5 months, about 1day to about 4 months, about 1 day to about 3 months, about 1 day toabout 10 weeks, about 1 day to about 2 months, about 1 day to about 6weeks, about 1 day to about 1 month, about 1 day to about 25 days, about1 day to about 20 days, about 1 day to about 15 days, about 1 day toabout 10 days, about 1 day to about 5 days, about 2 days to about 1year, about 5 days to about 1 year, about 10 days to about 1 year, about15 days to about 1 year, about 20 days to about 1 year, about 25 days toabout 1 year, about 1 month to about 1 year, about 6 weeks to about 1year, about 2 months to about 1 year, about 3 months to about 1 year,about 4 months to about 1 year, about 5 months to about 1 year, about 6months to about 1 year, about 7 months to about 1 year, about 8 monthsto about 1 year, about 9 months to about 1 year, about 10 months toabout 1 year, about 11 months to about 1 year, about 1 day to about 7days, about 1 day to about 14 days, about 5 days to about 10 days, about5 day to about 20 days, about 10 days to about 20 days, about 15 days toabout 1 month, about 15 days to about 2 months, about 1 week to about 1month, about 2 weeks to about 1 month, about 1 month to about 3 months,about 3 months to about 6 months, about 4 months to about 6 months,about 5 months to about 8 months, or about 7 months to about 9 months.In some embodiments of these methods, the subject can be previouslyidentified as having a cancer having a dysregulated FGFR gene (e.g., anyof the examples of a dysregulated FGFR gene described herein). In someembodiments of these methods, a subject can have been previouslydiagnosed as having any of the types of cancer described herein. In someembodiments of these methods, the subject can have one or moremetastases (e.g., one or more brain metastases).

In some of the above embodiments, the cfDNA comprises ctDNA such asFGFR-associated ctDNA. For example, the cfDNA is ctDNA such asFGFR-associated ctDNA. In some embodiments, at least some portion ofcfDNA is determined to be FGFR-associated ctDNA, for example, asequenced and/or quantified amount of the total cfDNA is determined tohave a FGFR fusion and/or a FGFR resistance mutation. In someembodiments provided herein, circulating tumor DNA can be used tomonitor the responsiveness of a subject to a particular therapy (e.g., afirst FGFR inhibitor, a second FGFR inhibitor, or a compound of FormulaI or a pharmaceutically acceptable salt or solvate thereof). Forexample, prior to starting treatment with a therapy as described herein(e.g., a first FGFR inhibitor, a second FGFR inhibitor, or a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof), abiological sample can be obtained from the subject and the level ofcirculating tumor DNA determined in the biological sample. This samplecan be considered a base-line sample. The subject can then beadministered one or more doses of a therapy as described herein (e.g., afirst FGFR inhibitor, a second FGFR inhibitor, or a compound of FormulaI or a pharmaceutically acceptable salt or solvate thereof) and thelevels of circulating tumor DNA can be monitored (e.g., after the firstdose, second dose, third dose, etc. or after one week, two weeks, threeweeks, four weeks, etc.). If the level of circulating tumor DNA is lowerthan the baseline sample (e.g., a 1% to about a 99% reduction, a 1% toabout a 95% reduction, a 1% to about a 90% reduction, a 1% to about a85% reduction, a 1% to about a 80% reduction, a 1% to about a 75%reduction, a 1% reduction to about a 70% reduction, a 1% reduction toabout a 65% reduction, a 1% reduction to about a 60% reduction, a 1%reduction to about a 55% reduction, a 1% reduction to about a 50%reduction, a 1% reduction to about a 45% reduction, a 1% reduction toabout a 40% reduction, a 1% reduction to about a 35% reduction, a 1%reduction to about a 30% reduction, a 1% reduction to about a 25%reduction, a 1% reduction to about a 20% reduction, a 1% reduction toabout a 15% reduction, a 1% reduction to about a 10% reduction, a 1% toabout a 5% reduction, about a 5% to about a 99% reduction, about a 10%to about a 99% reduction, about a 15% to about a 99% reduction, about a20% to about a 99% reduction, about a 25% to about a 99% reduction,about a 30% to about a 99% reduction, about a 35% to about a 99%reduction, about a 40% to about a 99% reduction, about a 45% to about a99% reduction, about a 50% to about a 99% reduction, about a 55% toabout a 99% reduction, about a 60% to about a 99% reduction, about a 65%to about a 99% reduction, about a 70% to about a 99% reduction, about a75% to about a 95% reduction, about a 80% to about a 99% reduction,about a 90% reduction to about a 99% reduction, about a 95% to about a99% reduction, about a 5% to about a 10% reduction, about a 5% to abouta 25% reduction, about a 10% to about a 30% reduction, about a 20% toabout a 40% reduction, about a 25% to about a 50% reduction, about a 35%to about a 55% reduction, about a 40% to about a 60% reduction, about a50% reduction to about a 75% reduction, about a 60% reduction to about80% reduction, or about a 65% to about a 85% reduction, etc.), this isindicative of responsiveness to the therapy. In some embodiments, thelevel of circulating tumor DNA is reduced such that it is below thedetection limit of the instrument. In some embodiments, the level ofcirculating tumor DNA in a biological sample obtained from the subject(n) is compared to the sample taken just previous (n−1). If the level ofcirculating tumor DNA in the n sample is lower than the n−1 sample(e.g., a 1% to about a 99% reduction, a 1% to about a 95% reduction, a1% to about a 90% reduction, a 1% to about a 85% reduction, a 1% toabout a 80% reduction, a 1% to about a 75% reduction, a 1% reduction toabout a 70% reduction, a 1% reduction to about a 65% reduction, a 1%reduction to about a 60% reduction, a 1% reduction to about a 55%reduction, a 1% reduction to about a 50% reduction, a 1% reduction toabout a 45% reduction, a 1% reduction to about a 40% reduction, a 1%reduction to about a 35% reduction, a 1% reduction to about a 30%reduction, a 1% reduction to about a 25% reduction, a 1% reduction toabout a 20% reduction, a 1% reduction to about a 15% reduction, a 1%reduction to about a 10% reduction, a 1% to about a 5% reduction, abouta 5% to about a 99% reduction, about a 10% to about a 99% reduction,about a 15% to about a 99% reduction, about a 20% to about a 99%reduction, about a 25% to about a 99% reduction, about a 30% to about a99% reduction, about a 35% to about a 99% reduction, about a 40% toabout a 99% reduction, about a 45% to about a 99% reduction, about a 50%to about a 99% reduction, about a 55% to about a 99% reduction, about a60% to about a 99% reduction, about a 65% to about a 99% reduction,about a 70% to about a 99% reduction, about a 75% to about a 95%reduction, about a 80% to about a 99% reduction, about a 90% reductionto about a 99% reduction, about a 95% to about a 99% reduction, about a5% to about a 10% reduction, about a 5% to about a 25% reduction, abouta 10% to about a 30% reduction, about a 20% to about a 40% reduction,about a 25% to about a 50% reduction, about a 35% to about a 55%reduction, about a 40% to about a 60% reduction, about a 50% reductionto about a 75% reduction, about a 60% reduction to about 80% reduction,or about a 65% to about a 85% reduction, etc.), this is indicative ofresponsiveness to the therapy. In some embodiments, the level ofcirculating tumor DNA is reduced such that it is below the detectionlimit of the instrument. In the case of responsiveness to therapy, thesubject can to be administered one or more doses of the therapy and thecirculating tumor DNA can be continued to be monitored.

If the level of circulating tumor DNA in the sample is higher than thebaseline (e.g., a 1% to about a 99% increase, a 1% to about a 95%increase, a 1% to about a 90% increase, a 1% to about a 85% increase, a1% to about a 80% increase, a 1% to about a 75% increase, a 1% increaseto about a 70% increase, a 1% increase to about a 65% increase, a 1%increase to about a 60% increase, a 1% increase to about a 55% increase,a 1% increase to about a 50% increase, a 1% increase to about a 45%increase, a 1% increase to about a 40% increase, a 1% increase to abouta 35% increase, a 1% increase to about a 30% increase, a 1% increase toabout a 25% increase, a 1% increase to about a 20% increase, a 1%increase to about a 15% increase, a 1% increase to about a 10% increase,a 1% to about a 5% increase, about a 5% to about a 99% increase, about a10% to about a 99% increase, about a 15% to about a 99% increase, abouta 20% to about a 99% increase, about a 25% to about a 99% increase,about a 30% to about a 99% increase, about a 35% to about a 99%increase, about a 40% to about a 99% increase, about a 45% to about a99% increase, about a 50% to about a 99% increase, about a 55% to abouta 99% increase, about a 60% to about a 99% increase, about a 65% toabout a 99% increase, about a 70% to about a 99% increase, about a 75%to about a 95% increase, about a 80% to about a 99% increase, about a90% increase to about a 99% increase, about a 95% to about a 99%increase, about a 5% to about a 10% increase, about a 5% to about a 25%increase, about a 10% to about a 30% increase, about a 20% to about a40% increase, about a 25% to about a 50% increase, about a 35% to abouta 55% increase, about a 40% to about a 60% increase, about a 50%increase to about a 75% increase, about a 60% increase to about 80%increase, or about a 65% to about a 85% increase, etc.), this can beindicative of resistance to the therapy. If the level of circulatingtumor DNA in the n sample is higher than the n−1 sample (e.g., a 1% toabout a 99% increase, a 1% to about a 95% increase, a 1% to about a 90%increase, a 1% to about a 85% increase, a 1% to about a 80% increase, a1% to about a 75% increase, a 1% increase to about a 70% increase, a 1%increase to about a 65% increase, a 1% increase to about a 60% increase,a 1% increase to about a 55% increase, a 1% increase to about a 50%increase, a 1% increase to about a 45% increase, a 1% increase to abouta 40% increase, a 1% increase to about a 35% increase, a 1% increase toabout a 30% increase, a 1% increase to about a 25% increase, a 1%increase to about a 20% increase, a 1% increase to about a 15% increase,a 1% increase to about a 10% increase, a 1% to about a 5% increase,about a 5% to about a 99% increase, about a 10% to about a 99% increase,about a 15% to about a 99% increase, about a 20% to about a 99%increase, about a 25% to about a 99% increase, about a 30% to about a99% increase, about a 35% to about a 99% increase, about a 40% to abouta 99% increase, about a 45% to about a 99% increase, about a 50% toabout a 99% increase, about a 55% to about a 99% increase, about a 60%to about a 99% increase, about a 65% to about a 99% increase, about a70% to about a 99% increase, about a 75% to about a 95% increase, abouta 80% to about a 99% increase, about a 90% increase to about a 99%increase, about a 95% to about a 99% increase, about a 5% to about a 10%increase, about a 5% to about a 25% increase, about a 10% to about a 30%increase, about a 20% to about a 40% increase, about a 25% to about a50% increase, about a 35% to about a 55% increase, about a 40% to abouta 60% increase, about a 50% increase to about a 75% increase, about a60% increase to about 80% increase, or about a 65% to about a 85%increase, etc.), this can be indicative of resistance to the therapy.When resistance to therapy is suspected, the subject can undergo one ormore of imaging, biopsy, surgery, or other diagnostic tests. In someembodiments, when resistance to the therapy is suspected, the subjectcan be administered (either as a monotherapy or in combination with theprevious therapy) a compound capable of treating a FGFR inhibitorresistance (e.g., a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof). See, for example, Cancer Discov;7(12); 1368-70 (2017); and Cancer Discov; 7(12); 1394-403 (2017).

In some embodiments provided herein, a protein biomarker can be used tomonitor the responsiveness of a subject to a particular therapy (e.g., afirst FGFR inhibitor, a second FGFR inhibitor, or a compound of FormulaI or a pharmaceutically acceptable salt or solvate thereof). Forexample, prior to starting treatment with a therapy as described herein(e.g., a first FGFR inhibitor, a second FGFR inhibitor, or a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof), abiological sample can be obtained from the subject and the level of aprotein biomarker can be determined in the biological sample. Thissample can be considered a base-line sample. The subject can then beadministered one or more doses of a therapy as described herein (e.g., afirst FGFR inhibitor, a second FGFR inhibitor, or a compound of FormulaI or a pharmaceutically acceptable salt or solvate thereof) and thelevels of the protein biomarker can be monitored (e.g., after the firstdose, second dose, third dose, etc. or after one week, two weeks, threeweeks, four weeks, etc.). If the level of the protein biomarker is lowerthan the baseline sample (e.g., a 1% to about a 99% reduction, a 1% toabout a 95% reduction, a 1% to about a 90% reduction, a 1% to about a85% reduction, a 1% to about a 80% reduction, a 1% to about a 75%reduction, a 1% reduction to about a 70% reduction, a 1% reduction toabout a 65% reduction, a 1% reduction to about a 60% reduction, a 1%reduction to about a 55% reduction, a 1% reduction to about a 50%reduction, a 1% reduction to about a 45% reduction, a 1% reduction toabout a 40% reduction, a 1% reduction to about a 35% reduction, a 1%reduction to about a 30% reduction, a 1% reduction to about a 25%reduction, a 1% reduction to about a 20% reduction, a 1% reduction toabout a 15% reduction, a 1% reduction to about a 10% reduction, a 1% toabout a 5% reduction, about a 5% to about a 99% reduction, about a 10%to about a 99% reduction, about a 15% to about a 99% reduction, about a20% to about a 99% reduction, about a 25% to about a 99% reduction,about a 30% to about a 99% reduction, about a 35% to about a 99%reduction, about a 40% to about a 99% reduction, about a 45% to about a99% reduction, about a 50% to about a 99% reduction, about a 55% toabout a 99% reduction, about a 60% to about a 99% reduction, about a 65%to about a 99% reduction, about a 70% to about a 99% reduction, about a75% to about a 95% reduction, about a 80% to about a 99% reduction,about a 90% reduction to about a 99% reduction, about a 95% to about a99% reduction, about a 5% to about a 10% reduction, about a 5% to abouta 25% reduction, about a 10% to about a 30% reduction, about a 20% toabout a 40% reduction, about a 25% to about a 50% reduction, about a 35%to about a 55% reduction, about a 40% to about a 60% reduction, about a50% reduction to about a 75% reduction, about a 60% reduction to about80% reduction, or about a 65% to about a 85% reduction etc.), this isindicative of responsiveness to the therapy. In some embodiments, thelevel of the protein biomarker is reduced such that it is below thedetection limit of the instrument. In some embodiments, the level of theprotein biomarker in a biological sample obtained from the subject (n)is compared to the sample taken just previous (n-1). If the level of theprotein biomarker in the n sample is lower than the n−1 sample (e.g., a1% to about a 99% reduction, a 1% to about a 95% reduction, a 1% toabout a 90% reduction, a 1% to about a 85% reduction, a 1% to about a80% reduction, a 1% to about a 75% reduction, a 1% reduction to about a70% reduction, a 1% reduction to about a 65% reduction, a 1% reductionto about a 60% reduction, a 1% reduction to about a 55% reduction, a 1%reduction to about a 50% reduction, a 1% reduction to about a 45%reduction, a 1% reduction to about a 40% reduction, a 1% reduction toabout a 35% reduction, a 1% reduction to about a 30% reduction, a 1%reduction to about a 25% reduction, a 1% reduction to about a 20%reduction, a 1% reduction to about a 15% reduction, a 1% reduction toabout a 10% reduction, a 1% to about a 5% reduction, about a 5% to abouta 99% reduction, about a 10% to about a 99% reduction, about a 15% toabout a 99% reduction, about a 20% to about a 99% reduction, about a 25%to about a 99% reduction, about a 30% to about a 99% reduction, about a35% to about a 99% reduction, about a 40% to about a 99% reduction,about a 45% to about a 99% reduction, about a 50% to about a 99%reduction, about a 55% to about a 99% reduction, about a 60% to about a99% reduction, about a 65% to about a 99% reduction, about a 70% toabout a 99% reduction, about a 75% to about a 95% reduction, about a 80%to about a 99% reduction, about a 90% reduction to about a 99%reduction, about a 95% to about a 99% reduction, about a 5% to about a10% reduction, about a 5% to about a 25% reduction, about a 10% to abouta 30% reduction, about a 20% to about a 40% reduction, about a 25% toabout a 50% reduction, about a 35% to about a 55% reduction, about a 40%to about a 60% reduction, about a 50% reduction to about a 75%reduction, about a 60% reduction to about 80% reduction, or about a 65%to about a 85% reduction, etc.), this is indicative of responsiveness tothe therapy. In some embodiments, the level of the protein biomarker isreduced such that it is below the detection limit of the instalment. Inthe case of responsiveness to therapy, the subject can to beadministered one or more doses of the therapy and the protein biomarkercan continue to be monitored.

If the level of the protein biomarker in the sample is higher than thebaseline (e.g., a 1% to about a 99% increase, a 1% to about a 95%increase, a 1% to about a 90% increase, a 1% to about a 85% increase, a1% to about a 80% increase, a 1% to about a 75% increase, a 1% increaseto about a 70% increase, a 1% increase to about a 65% increase, a 1%increase to about a 60% increase, a 1% increase to about a 55% increase,a 1% increase to about a 50% increase, a 1% increase to about a 45%increase, a 1% increase to about a 40% increase, a 1% increase to abouta 35% increase, a 1% increase to about a 30% increase, a 1% increase toabout a 25% increase, a 1% increase to about a 20% increase, a 1%increase to about a 15% increase, a 1% increase to about a 10% increase,a 1% to about a 5% increase, about a 5% to about a 99% increase, about a10% to about a 99% increase, about a 15% to about a 99% increase, abouta 20% to about a 99% increase, about a 25% to about a 99% increase,about a 30% to about a 99% increase, about a 35% to about a 99%increase, about a 40% to about a 99% increase, about a 45% to about a99% increase, about a 50% to about a 99% increase, about a 55% to abouta 99% increase, about a 60% to about a 99% increase, about a 65% toabout a 99% increase, about a 70% to about a 99% increase, about a 75%to about a 95% increase, about a 80% to about a 99% increase, about a90% increase to about a 99% increase, about a 95% to about a 99%increase, about a 5% to about a 10% increase, about a 5% to about a 25%increase, about a 10% to about a 30% increase, about a 20% to about a40% increase, about a 25% to about a 50% increase, about a 35% to abouta 55% increase, about a 40% to about a 60% increase, about a 50%increase to about a 75% increase, about a 60% increase to about 80%increase, or about a 65% to about a 85% increase, etc.), this can beindicative of resistance to the therapy. If the level of the proteinbiomarker in the n sample is higher than the n-1 sample (e.g., a 1% toabout a 99% increase, a 1% to about a 95% increase, a 1% to about a 90%increase, a 1% to about a 85% increase, a 1% to about a 80% increase, a1% to about a 75% increase, a 1% increase to about a 70% increase, a 1%increase to about a 65% increase, a 1% increase to about a 60% increase,a 1% increase to about a 55% increase, a 1% increase to about a 50%increase, a 1% increase to about a 45% increase, a 1% increase to abouta 40% increase, a 1% increase to about a 35% increase, a 1% increase toabout a 30% increase, a 1% increase to about a 25% increase, a 1%increase to about a 20% increase, a 1% increase to about a 15% increase,a 1% increase to about a 10% increase, a 1% to about a 5% increase,about a 5% to about a 99% increase, about a 10% to about a 99% increase,about a 15% to about a 99% increase, about a 20% to about a 99%increase, about a 25% to about a 99% increase, about a 30% to about a99% increase, about a 35% to about a 99% increase, about a 40% to abouta 99% increase, about a 45% to about a 99% increase, about a 50% toabout a 99% increase, about a 55% to about a 99% increase, about a 60%to about a 99% increase, about a 65% to about a 99% increase, about a70% to about a 99% increase, about a 75% to about a 95% increase, abouta 80% to about a 99% increase, about a 90% increase to about a 99%increase, about a 95% to about a 99% increase, about a 5% to about a 10%increase, about a 5% to about a 25% increase, about a 10% to about a 30%increase, about a 20% to about a 40% increase, about a 25% to about a50% increase, about a 35% to about a 55% increase, about a 40% to abouta 60% increase, about a 50% increase to about a 75% increase, about a60% increase to about 80% increase, or about a 65% to about a 85%increase etc.), this can be indicative of resistance to the therapy.When resistance to therapy is suspected, the subject can undergo one ormore of imaging, biopsy, surgery, or other diagnostic tests. In someembodiments, when resistance to the therapy is suspected, the subjectcan be administered (either as a monotherapy or in combination with theprevious therapy) a compound capable of treating a FGFR inhibitorresistance (e.g., a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof).

In some embodiments, one or more biomarkers are monitored. In someembodiments, the one or more biomarkers include one or more proteinbiomarkers. The particular biomarkers to be monitored can depend on thetype of cancer and can be readily identified by one having ordinaryskill in the art. Non-limiting examples of protein biomarkers include:CA125, carcinoembryonic antigen (CEA), calcitonin, CA19-9, prolactin,hepatocyte growth factor, osteopontin, myeloperoxidase, tissue inhibitorof metalloproteinases 1, angiopoietin-1 (Ang-1), cytokeratin 19 (CK-19),tissue inhibitor of metalloproteinase-1 (TIMP-1), chitinase 3 like-1(YKL-40), galectin-3 (GAL-3), CYFRA 21-1 (cytokeratins), EPCAM(epithelial cell adhesion molecule), ProGRP (pro-gastrin-releasingpeptide), and CEACAM (carcinoembryonic antigen). See, for example, CohenJ D, Li L, Wang Y, et al. Detection and localization of surgicallyresectable cancers with a multi-analyte blood test. Science; Publishedonline 18 Jan. 2018. pii: eaar3247. DOI: 10.1126/science.aar3247; FawazM Makki et al. Serum biomarkers of papillary thyroid cancer. JOtolaryngol Head Neck Surg. 2013; 42(1): 16; Tatiana N. Zamay et al.Current and Prospective Protein Biomarkers of Lung Cancer. Cancers(Basel). 2017 November; 9(11): 155; Leiblich, Recent Developments in theSearch for Urinary Biomarkers in Bladder Cancer Curr. Urol. Rep. 2017;18(12): 100; and Santoni et al, Urinary Markers in Bladder Cancer: AnUpdate Front. Oncol. 2018; 8: 362. In some embodiments, the cancer isbladder cancer and the biomarkers are urinary extracellular vesicles. Insome embodiments, the cancer is bladder cancer, and the proteinbiomarkers are urinary protein biomarkers. In some embodiments, thecancer is bladder cancer and the protein biomarkers includealpha-1-anti-trypsin. In some embodiments, the cancer is bladder cancerand the protein biomarkers include H2B1K. In some embodiments, thecancer is bladder cancer and the protein biomarkers include BcLA-1 orBCLA-4. In some embodiments, the cancer is bladder cancer, and theprotein biomarkers include aurora A kinase. In some embodiments, thecancer is bladder cancer, and the protein biomarkers include leukocytecell adhesion molecule (ALCAM). In some embodiments, the cancer isbladder cancer and the protein biomarkers include nicotinamideN-methyltransferase. In some embodiments, the cancer is bladder cancerand the protein biomarkes include apurinic/apyrimidinic endonuclease1/redox factor-1 (APE/Ref-1). In some embodiments, the cancer is bladdercancer, and the protein biomarkers include cytokeratin-20 (CK20). Insome embodiments, the cancer is bladder cancer and the proteinbiomarkers include one or more of apolipoproteins A1, A2, B, C2, C3, andE. In some embodiments, the cancer is bladder cancer and the proteinbiomarkers include one or more of uromodulin, collagen α-1 (I), collagenα-1 (III), and membrane-associated progesterone receptor component 1. Insome embodiments, the cancer is bladder cancer and the proteinbiomarkers include one or more of IL-8, MM P-9/10, ANG, APOE, SDC-1,α1AT, PAI-1, VEGFA, and CA9. In some embodiments, cancer is bladdercancer and the protein biomarkers include one or more of midkine (MDK)and synudein G or MDK, ZAG2 and CEACAM1, angiogenin, and dusterin. Insome embodiments, the cancer is bladder cancer and the proteinbiomarkers include one or more of CK20 and Insulin Like Growth Factor II(IGFII). In some embodiments, the cancer is bladder cancer and theprotein biomarkers include one or more of HAI-1 and Epcam. In someembodiments, the cancer is bladder cancer and the protein biomarkersinclude survivin. In some embodiments, the cancer is bladder cancer andthe protein biomarkers include Snail. In some embodiments, the cancer isbladder cancer and the protein biomarkers include CD44.

Also provided herein are methods of treating a FGFR-associated cancer ina subject that include (a) administering one or more (e.g., two or more,three or more, four or more, five or more, or ten or more) doses of afirst FGFR kinase inhibitor to a subject identified or diagnosed ashaving a FGFR-associated cancer (e.g., any of the types ofFGFR-associated cancers described herein)(e.g., identified or diagnosedas having a FGFR-associated cancer using any of the exemplary methodsdescribed herein or known in the art); (b) after step (a), determining alevel of circulating tumor DNA in a biological sample (e.g., abiological sample comprising blood, serum, or plasma) obtained from thesubject; (c) administering a therapeutically effective amount of asecond FGFR inhibitor or a compound of Formula I, or a pharmaceuticallyacceptable salt or solvate thereof as a monotherapy or in conjunctionwith an additional therapy or therapeutic agent to a subject identifiedas having about the same or an elevated level of circulating tumor DNAas compared to a reference level of circulating tumor DNA (e.g., any ofthe reference levels of circulating tumor DNA described herein). In someexamples of these methods, the reference level of circulating tumor DNAis a level of circulating tumor DNA in a biological sample obtained fromthe subject prior to step (a). Some embodiments of these methods furtherinclude determining the level of circulating tumor DNA in the biologicalsample obtained from the subject prior to step (a). In some examples ofthese methods, the reference level of circulating tumor DNA is athreshold level of circulating tumor DNA (e.g., an average level ofcirculating tumor DNA in a population of subjects having a similarFGFR-associated cancer and having a similar stage of the FGFR-associatedcancer, but receiving a non-effective treatment or a placebo, or not yetreceiving therapeutic treatment, or a level of circulating tumor DNA ina subject having a similar FGFR-associated cancer and having a similarstage of the FGFR-associated cancer, but receiving a non-effectivetreatment or a placebo, or not yet receiving therapeutic treatment). Insome examples of these methods, the first FGFR inhibitor is selectedfrom the group of: ARQ-087, ASP5878, AZD4547, B-701, BAY1179470,BAY1187982, BGJ398, brivanib, Debio 1347, dovitinib, E7090, erdafitinib,FPA144, HMPL-453, INCB054828, lenvatinib, lucitanib, LY3076226,MAX-40279, nintedanib, orantinib, pemigatinib, ponatinib, PRN1371,rogaratinib, sulfatinib, and TAS-120.

Also provided herein are methods of treating a FGFR-associated cancer ina subject that include administering a therapeutically effective amountof a compound of Formula I, or a pharmaceutically acceptable salt orsolvate thereof, to a subject (i) identified or diagnosed as having aFGFR-associated cancer (e.g., any of the types of FGFR-associatedcancers described herein) (e.g., identified or diagnosed as having aFGFR-associated cancer using any of the exemplary methods describedherein or known in the art), (ii) previously administered one or more(e.g., two or more, three or more, four or more, five or more, or ten ormore) doses of a second FGFR kinase inhibitor, and (ii) after the prioradministration of the one or more doses of the second FGFR kinaseinhibitor, identified as having about the same or an elevated level ofcirculating tumor DNA as compared to a reference level of circulatingtumor DNA (e.g., any of the reference levels of circulating tumor DNAdescribed herein or known in the art). In some embodiments of thesemethods, the reference level of circulating tumor DNA is a level ofcirculating tumor DNA in a biological sample (e.g., a biological samplecomprising blood, plasma, or serum) obtained from the subject prior tothe administration of the one or more doses of the second FGFR kinaseinhibitor. Some embodiments of these methods further include determiningthe level of circulating tumor DNA in the biological sample obtainedfrom the subject prior to administration of the one or more doses of thesecond FGFR kinase inhibitor. In some examples of these methods, thereference level of circulating tumor DNA is a threshold level ofcirculating tumor DNA (e.g., an average level of circulating tumor DNAin a population of subjects having a similar FGFR-associated cancer andhaving a similar stage of the FGFR-associated cancer, but receiving anon-effective treatment or a placebo, or not yet receiving therapeutictreatment, or a level of circulating tumor DNA in a subject having asimilar FGFR-associated cancer and having a similar stage of theFGFR-associated cancer, but receiving a non-effective treatment or aplacebo, or not yet receiving therapeutic treatment). In someembodiments of these methods, the second FGFR kinase inhibitor isselected from the group consisting of: ARQ-087, ASP5878, AZD4547, B-701,BAY1179470, BAY1187982, BGJ398, brivanib, Debio 1347, dovitinib, E7090,erdafitinib, FPA144, HMPL-453, INCB054828, lenvatinib, lucitanib,LY3076226, MAX-40279, nintedanib, orantinib, pemigatinib, ponatinib,PRN1371, rogaratinib, sulfatinib, and TAS-120.

Also provided herein are methods of treating a FGFR-associated cancer ina subject that include: (a) administering one or more doses of acompound of Formula I, or a pharmaceutically acceptable salt or solvatethereof, as a monotherapy to a subject identified or diagnosed as havinga FGFR-associated cancer (e.g., any of the types of FGFR-associatedcancer described herein) (e.g., a subject identified or diagnosed ashaving a FGFR-associated cancer using any of the methods describedherein or known in the art); (b) after step (a), determining a level ofcirculating tumor DNA in a biological sample (e.g., a biological samplecomprising blood, serum, or plasma) obtained from the subject; (c)administering a therapeutically effective amount of a compound ofFormula I, or a pharmaceutically acceptable salt or solvate thereof, andan additional therapy or therapeutic agent (e.g., any of the additionaltherapies or therapeutic agents of a FGFR-associated cancer describedherein or known in the art) to a subject identified as having about thesame or an elevated level of circulating tumor DNA as compared to areference level of circulating tumor DNA (e.g., any of the exemplaryreference levels of circulating tumor DNA described herein or known inthe art). In some embodiments of these methods, the additionaltherapeutic agent is a second FGFR kinase inhibitor (e.g., a FGFR kinaseinhibitor selected from the group of: ARQ-087, ASP5878, AZD4547, B-701,BAY1179470, BAY1187982, BGJ398, brivanib, Debio 1347, dovitinib, E7090,erdafitinib, FPA144, HMPL-453, INCB054828, lenvatinib, lucitanib,LY3076226, MAX-40279, nintedanib, orantinib, pemigatinib, ponatinib,PRN1371, rogaratinib, sulfatinib, and TAS-120. In some examples of anyof these methods, the additional therapy or therapeutic agent comprisesone or more of: radiation therapy, a chemotherapeutic agent (e.g., anyof the exemplary chemotherapeutic agents described herein or known inthe art), a checkpoint inhibitor (e.g., any of the exemplary checkpointinhibitors described herein or known in the art), surgery (e.g., atleast partial resection of the tumor) and one or more other kinaseinhibitors (e.g., any of the exemplary kinase inhibitors describedherein or known in the art). In some examples of these methods, thereference level of circulating tumor DNA is a level of circulating tumorDNA in a biological sample (e.g., a biological sample comprising blood,serum, or plasma) obtained from the subject prior to step (a). In someexamples of these methods, the reference level of circulating tumor DNAis a threshold level of circulating tumor DNA (e.g., an average level ofcirculating tumor DNA in a population of subjects having a similarFGFR-associated cancer and having a similar stage of the FGFR-associatedcancer, but receiving a non-effective treatment or a placebo, or not yetreceiving therapeutic treatment, or a level of circulating tumor DNA ina subject having a similar FGFR-associated cancer and having a similarstage of the FGFR-associated cancer, but receiving a non-effectivetreatment or a placebo, or not yet receiving therapeutic treatment).

Also provided herein are methods of treating a FGFR-associated cancer ina subject that include: administering a therapeutically effective amountof a compound of Formula I, or a pharmaceutically acceptable salt orsolvate thereof, and an additional therapy or therapeutic agent to asubject (i) identified or diagnosed as having a FGFR-associated cancer(e.g., any of the types of FGFR-associated cancer described herein)(e.g., a subject identified or diagnosed as having a FGFR-associatedcancer using any of the methods described herein or known in the art),(ii) previously administered one or more doses of the compound ofFormula I, or the therapeutically acceptable salt or solvate thereof, asa monotherapy, and (ii) after administration of the one or more (e.g.,two or more, three or more, four or more, five or more, or ten or more)doses of the compound of Formula I, or the therapeutically acceptablesalt or solvate thereof, as a monotherapy, identified as having aboutthe same or an elevated level of circulating tumor DNA as compared to areference level of circulating tumor DNA (e.g., any of the exemplaryreference levels of circulating tumor DNA described herein). In someembodiments of these methods, the reference level of circulating tumorDNA is a level of circulating tumor DNA in a biological sample obtainedfrom the subject prior to administration of the one or more (e.g., twoor more, three or more, four or more, five or more, or ten or more)doses of the compound of Formula I, or the pharmaceutically acceptablesalt or solvate thereof, as a monotherapy. Some embodiments of thesemethods further include determining the level of circulating tumor DNAin the biological sample obtained from the subject prior toadministration of the one or more doses of the compound of Formula I, orthe pharmaceutically acceptable salt or solvate thereof, as amonotherapy. In some examples of these methods, the reference level ofcirculating tumor DNA is a threshold level of circulating tumor DNA(e.g., an average level of circulating tumor DNA in a population ofsubjects having a similar FGFR-associated cancer and having a similarstage of the FGFR-associated cancer, but receiving a non-effectivetreatment or a placebo, or not yet receiving therapeutic treatment, or alevel of circulating tumor DNA in a subject having a similarFGFR-associated cancer and having a similar stage of the FGFR-associatedcancer, but receiving a non-effective treatment or a placebo, or not yetreceiving therapeutic treatment). In some embodiments of this method,the additional therapeutic agent is a second FGFR kinase inhibitor(e.g., a second FGFR kinase inhibitor selected from the group ofARQ-087, ASP5878, AZD4547, B-701, BAY1179470, BAY1187982, BGJ398,brivanib, Debio 1347, dovitinib, E7090, erdafitinib, FPA144, HMPL-453,INCB054828, lenvatinib, lucitanib, LY3076226, MAX-40279, nintedanib,orantinib, pemigatinib, ponatinib, PRN1371, rogaratinib, sulfatinib, andTAS-120. In some embodiments of these methods, the additional therapy ortherapeutic agent includes one or more of radiation therapy, achemotherapeutic agent (e.g., any of the exemplary chemotherapeuticagents described herein or known in the art), a checkpoint inhibitor(e.g., any of the exemplary checkpoint inhibitors described herein orknown in the art), surgery (e.g., at least partial resection of thetumor), and one or more other kinase inhibitors (e.g., any of the kinaseinhibitors described herein or known in the art).

Also provided herein are methods of selecting a treatment for a subjectthat include: selecting a therapeutically effective amount of a compoundof Formula I, or a pharmaceutically acceptable salt or solvate thereof,for a subject (i) identified or diagnosed as having a FGFR-associatedcancer (e.g., any of the FGFR-associated cancers described herein)(e.g., a subject identified or diagnosed as having a FGFR-associatedcancer using any of the methods described herein or known in the art),(ii) previously administered one or more (e.g., two or more, three ormore, four or more, five or more, or ten or more) doses of a second FGFRkinase inhibitor (e.g., any of the FGFR kinase inhibitors describedherein or known in the art), and (ii) after administration of the one ormore doses of the second FGFR kinase inhibitor, identified as havingabout the same or an elevated level of circulating tumor DNA as comparedto a reference level of circulating tumor DNA. In some embodiments ofany of these methods, the reference level of circulating tumor DNA is alevel of circulating tumor DNA in a biological sample (e.g., abiological sample comprising blood, serum, or plasma) obtained from thesubject prior to administration of the one or more doses of the secondFGFR kinase inhibitor. Some embodiments of these methods further includedetermining the level of circulating tumor DNA in the biological sampleobtained from the subject prior to administration of the one or moredoses of the second FGFR kinase inhibitor. In some examples of thesemethods, the reference level of circulating tumor DNA is a thresholdlevel of circulating tumor DNA (e.g., an average level of circulatingtumor DNA in a population of subjects having a similar FGFR-associatedcancer and having a similar stage of the FGFR-associated cancer, butreceiving a non-effective treatment or a placebo, or not yet receivingtherapeutic treatment, or a level of circulating tumor DNA in a subjecthaving a similar FGFR-associated cancer and having a similar stage ofthe FGFR-associated cancer, but receiving a non-effective treatment or aplacebo, or not yet receiving therapeutic treatment). In someembodiments of any these methods, the second FGFR kinase inhibitor isselected from the group of ARQ-087, ASP5878, AZD4547, B-701, BAY1179470,BAY1187982, BGJ398, brivanib, Debio 1347, dovitinib, E7090, erdafitinib,FPA144, HMPL-453, INCB054828, lenvatinib, lucitanib, LY3076226,MAX-40279, nintedanib, orantinib, pemigatinib, ponatinib, PRN1371,rogaratinib, sulfatinib, and TAS-120.

Also provided herein are methods of selecting a treatment for a subjectthat include selecting a therapeutically effective amount of a compoundof Formula I, or a pharmaceutically acceptable salt or solvate thereof,and an additional therapy or therapeutic agent for a subject (i)identified or diagnosed as having a FGFR-associated cancer (e.g., any ofthe FGFR-associated cancers described herein or known in the art) (e.g.,a subject diagnosed or identified as having a FGFR-associated cancerusing any of the methods described herein or known in the art), (ii)previously administered one or more doses (e.g., two or more, three ormore, four or more, five or more, or ten or more) of the compound ofFormula I, or the therapeutically acceptable salt or solvate thereof, asa monotherapy, and (ii) after administration of the one or more doses ofthe compound of Formula I, or the therapeutically acceptable salt orsolvate thereof, identified as having about the same or an elevatedlevel of circulating tumor DNA as compared to a reference level ofcirculating tumor DNA. Some embodiments further include determining thelevel of circulating tumor DNA in the biological sample obtained fromthe subject prior to administration of the one or more doses of thecompound of Formula I, or the pharmaceutically acceptable salt orsolvate thereof, as a monotherapy. Some embodiments further includedetermining the level of circulating tumor DNA in the biological sampleobtained from the subject prior to administration of the one or moredoses of the compound of Formula I, or the pharmaceutically acceptablesalt or solvate thereof, as a monotherapy. In some examples of thesemethods, the reference level of circulating tumor DNA is a thresholdlevel of circulating tumor DNA (e.g., an average level of circulatingtumor DNA in a population of subjects having a similar FGFR-associatedcancer and having a similar stage of the FGFR-associated cancer, butreceiving a non-effective treatment or a placebo, or not yet receivingtherapeutic treatment, or a level of circulating tumor DNA in a subjecthaving a similar FGFR-associated cancer and having a similar stage ofthe FGFR-associated cancer, but receiving a non-effective treatment or aplacebo, or not yet receiving therapeutic treatment). In someembodiments of any of these methods, the additional therapeutic agent isa second FGFR kinase inhibitor (e.g., a second FGFR kinase inhibitorselected from the group of: ARQ-087, ASP5878, AZD4547, B-701,BAY1179470, BAY1187982, BGJ398, brivanib, Debio 1347, dovitinib, E7090,erdafitinib, FPA144, HMPL-453, INCB054828, lenvatinib, lucitanib,LY3076226, MAX-40279, nintedanib, orantinib, pemigatinib, ponatinib,PRN1371, rogaratinib, sulfatinib, and TAS-120). In some embodiments ofany of the methods described herein, the additional therapy ortherapeutic agent includes one or more of radiation therapy, achemotherapeutic agent (e.g., any of the examples of a chemotherapeuticagent described herein or known in the art), a checkpoint inhibitor(e.g., any of the checkpoint inhibitors described herein or known in theart), surgery (e.g., at least partial resection of the tumor), and oneor more other kinase inhibitors (e.g., any of the other kinaseinhibitors described herein or known in the art).

Also provided herein are methods of determining the efficacy of atreatment in a subject that include: (a) determining a first level ofcirculating tumor DNA in a biological sample (e.g., a biological sampleincluding blood, serum, or plasma) obtained from a subject identified ordiagnosed as having a FGFR-associated cancer at a first time point; (b)administering a treatment including one or more doses of a compound ofFormula I, or a pharmaceutically acceptable salt or solvate thereof tothe subject, after the first time point and before a second time point;(c) determining a second level of circulating tumor DNA in a biologicalsample (e.g., a biological sample comprising blood, serum, or plasma)obtained from the subject at the second time point; and (d) identifyingthat the treatment is effective in a subject determined to have adecreased second level of circulating tumor DNA as compared to the firstlevel of circulating tumor DNA; or identifying the treatment is noteffective in a subject determined to have about the same or an elevatedsecond level of circulating tumor DNA as compared to the first level ofcirculating tumor DNA. In some embodiments of these methods, the firsttime point and the second time point are about 1 week to about 1 yearapart (e.g., about 1 week to about 10 months, about 1 week to about 8months, about 1 week to about 6 months, about 1 week to about 4 months,about 1 week to about 3 months, about 1 week to about 2 months, about 1week to about 1 month, or about 1 week to about 2 weeks).

Also provided herein are methods of determining whether a subject hasdeveloped resistance to a treatment that include: (a) determining afirst level of circulating tumor DNA in a biological sample (e.g., abiological sample comprising blood, serum, or plasma) obtained from asubject identified or diagnosed as having a FGFR-associated cancer at afirst time point; (b) administering a treatment including one or more(e.g., two or more, three or more, four or more, five or more, or ten ormore) doses of a compound of Formula I, or a pharmaceutically acceptablesalt or solvate thereof to the subject, after the first time point andbefore a second time point; (c) determining a second level ofcirculating tumor DNA in a biological sample obtained from the subjectat the second time point; and (d) determining that a subject having adecreased second level of circulating tumor DNA as compared to the firstlevel of circulating tumor DNA has not developed resistance to thetreatment; or determining that a subject having about the same or anelevated second level of circulating tumor DNA as compared to the firstlevel of circulating tumor DNA has developed resistance to thetreatment. In some embodiments of these methods, the first time pointand the second time point are about 1 week to about 1 year apart (e.g.,about 1 week to about 10 months, about 1 week to about 8 months, about 1week to about 6 months, about 1 week to about 4 months, about 1 week toabout 3 months, about 1 week to about 2 months, about 1 week to about 1month, or about 1 week to about 2 weeks).

Exemplary methods for detecting circulating tumor DNA are described inMoati et al., Clin. Res. Hepatol. Gastroenterol. Apr. 4, 2018; Oussalahet al., EBioMedicine Mar. 28, 2018; Moon et al., Adv. Drug Deliv. Rev.Apr. 4, 2018; Solassaol et al., Clin. Chem. Lab. Med. Apr. 7, 2018;Arriola et al., Clin. Transl. Oncol. Apr. 5, 2018; Song et al., J. Circ.Biomark. Mar. 25, 2018; Aslibekyan et al., JAMA Cardiol. Apr. 4, 2018;Isbell et al., J. Tborac. Cardiovasc. Surg. Mar. 13, 2018; Boeckx etal., Clin. Colorectal Cancer Feb. 22, 2018; Anunobi et al., J. Surg.Res. Mar. 28, 2018; Tan et al., Medicine 97(13):e0197,2018; Reithdorf etal., Transl. Androl. Urol. 6(6):1090-1110,2017; Vokkmar et al., GenesChromosomes Cancer 57(3):123-139,2018; and Lu et al., Chronic Dis.Transl. Med. 2(4):223-230,2016. Additional methods for detectingcirculating tumor DNA are known in the art.

In the field of medical oncology, it is normal practice to use acombination of different forms of treatment to treat each subject withcancer. In medical oncology, the other component(s) of such conjointtreatment or therapy in addition to compositions provided herein may be,for example, surgery, radiotherapy, and chemotherapeutic agents, such asother kinase inhibitors, signal transduction inhibitors and/ormonoclonal antibodies. For example, a surgery may be open surgery orminimally invasive surgery.

In some embodiments, an additional therapeutic agent(s) is selected fromagents active against the downstream FGFR pathway, including, e.g., Ras,MEK, JNK, and p38 kinase inhibitor.

Compounds of Formula I therefore may also be useful as adjuvants tocancer treatment, that is, they can be used in combination with one ormore additional therapies or therapeutic agents, for example achemotherapeutic agent that works by the same or by a differentmechanism of action. In some embodiments, a compound of Formula I, or apharmaceutically acceptable salt thereof, can be used prior toadministration of an additional therapeutic agent or additional therapy.For example, a subject in need thereof can be administered one or moredoses of a compound of Formula I or a pharmaceutically acceptable saltthereof for a period of time and then under go at least partialresection of the tumor. In some embodiments, the treatment with one ormore doses of a compound of Formula I or a pharmaceutically acceptablesalt thereof reduces the size of the tumor (e.g., the tumor burden)prior to the at least partial resection of the tumor. In someembodiments, a subject has a cancer (e.g., a locally advanced ormetastatic tumor) that is refractory or intolerant to standard therapy(e.g., administration of a chemotherapeutic agent, such as a first FGFRinhibitor or a multikinase inhibitor, immunotherapy, radiation, or aplatinum-based agent (e.g., cisplatin)). In some embodiments, a subjecthas a cancer (e.g., a locally advanced or metastatic tumor) that isrefractory or intolerant to prior therapy (e.g., administration of achemotherapeutic agent, such as a first FGFR inhibitor or a multikinaseinhibitor, immunotherapy, radiation, or a platinum-based agent (e.g.,cisplatin)).

In some embodiments of any the methods described herein, the compound ofFormula I (or a pharmaceutically acceptable salt or solvate thereof) isadministered in combination with a therapeutically effective amount ofat least one additional therapeutic agent selected from one or moreadditional therapies or therapeutic (e.g., chemotherapeutic) agents.

Non-limiting examples of additional therapeutic agents include: otherFGFR-targeted therapeutic agents (i.e. a first or second FGFR kinaseinhibitor), other kinase inhibitors (e.g., receptor tyrosinekinase-targeted therapeutic agents (e.g., Trk inhibitors or EGFRinhibitors)), signal transduction pathway inhibitors, checkpointinhibitors, modulators of the apoptosis pathway (e.g. obatadax);cytotoxic chemotherapeutics, angiogenesis-targeted therapies,immune-targeted agents, including immunotherapy, and radiotherapy.

In some embodiments, an additional therapy or therapeutic agent caninclude a platinum coordination compound, for example, cisplatinoptionally combined with amifostine, carboplatin, or oxaliplatin. Insome embodiments, an additional therapy or therapeutic agent can includetaxane compounds for example paditaxel, paditaxel protein boundparticles (Abraxane™), or docetaxel. In some embodiments, an additionaltherapy or therapeutic agent can include topoisomerase I inhibitors suchas camptothecin compounds, for example, irinotecan, SN-38, topotecan,topotecan HCl. In some embodiments, an additional therapy or therapeuticagent can include topoisomerase II inhibitors such as anti-tumourepipodophyllotoxins or podophyllotoxin derivatives, for example,etoposide, etoposide phosphate, or teniposide. In some embodiments, anadditional therapy or therapeutic agent can include anti-tumour vincaalkaloids, for example, vinblastine, vincristine, vindesine, orvinorelbine. In some embodiments, an additional therapy or therapeuticagent can include anti-tumour nucleoside derivatives, for example,5-fluorouracil, leucovorin, gemcitabine, gemcitabine HCl, capecitabine,cladribine, fludarabine, or nelarabine. In some embodiments, anadditional therapy or therapeutic agent can include alkylating agentssuch as nitrogen mustard or nitrosourea, for example, cyclophosphamide,chlorambucil, carmustine, thiotepa, mephalan (melphalan), lomustine,semustine, altretamine, busulfan, dacarbazine, estramustine, ifosfamideoptionally in combination with mesna, pipobroman, procarbazine,streptozocin, telozolomide, or uracil. In some embodiments, anadditional therapy or therapeutic agent can include anti-tumouranthracydine derivatives, for example, daunorubicin, doxorubicinoptionally in combination with dexrazoxane, doxil, idarubicin,mitoxantrone, epirubicin, epirubicin HCl, or valrubicin. In someembodiments, an additional therapy or therapeutic agent can includetetracarcin derivatives, for example, tetrocarcin A. In someembodiments, an additional therapy or therapeutic agent can includeglucocorticoids, for example, prednisone or prednisolone. In someembodiments, an additional therapy or therapeutic agent can includeestrogen receptor antagonists or selective estrogen receptor modulatorsor inhibitors of estrogen synthesis, for example, tamoxifen,fulvestrant, toremifene, droloxifene, faslodex, raloxifene, orletrozole. In some embodiments, an additional therapy or therapeuticagent can include differentiating agents such as retinoids, vitamin D,or retinoic acid and retinoic acid metabolism blocking agents (RAMBA),for example, accutane. In some embodiments, an additional therapy ortherapeutic agent can include DNA methyl transferase inhibitors, forexample, azacytidine or decitabine. In some embodiments, an additionaltherapy or therapeutic agent can include antifolates, for example,premetrexed disodium. In some embodiments, an additional therapy ortherapeutic agent can include antibiotics, for example, antinomycin D,bleomycin, deoxycoformycin, mitomycin C, dactinomycin, carminomycin,daunomycin, levamisole, plicamycin, mithramycin. In some embodiments, anadditional therapy or therapeutic agent can include antimetabolites, forexample, dofarabine, aminopterin, cytosine arabinoside, methotrexate,azacitidine, cytarabine, floxuridine, pentostatin, or thioguanine. Insome embodiments, an additional therapy or therapeutic agent can includeapoptosis inducing agents and antiangiogenic agents such as Bd-2inhibitors, for example, YC137, BH 312, ABT 737, gossypol, HA 14-1, TW37, or decanoic acid. In some embodiments, an additional therapy ortherapeutic agent can include tubulin-binding agents, for example,combrestatin, colchicines, or nocodazole. In some embodiments, anadditional therapy or therapeutic agent can include famesyttransferaseinhibitors, for example, tipifarnib. In some embodiments, an additionaltherapy or therapeutic agent can include histone deacetylase (HDAC)inhibitors, for example, sodium butyrate, suberoylanilide hydroxamideacid (SAHA), depsipeptide (FR 901228), panobinostat, NVP-LAQ824,R306465, JNJ-26481585, trichostatin A, or vorinostat. In someembodiments, an additional therapy or therapeutic agent can includeinhibitors of the ubiquitin-proteasome pathway for example PS-341, MLN0.41, bortezomib, or carfilzomib. In some embodiments, an additionaltherapy or therapeutic agent can include Yondelis. In some embodiments,an additional therapy or therapeutic agent can include telomeraseinhibitors, for example, telomestatin. In some embodiments, anadditional therapy or therapeutic agent can include matrixmetalloproteinase inhibitors, for example, batimastat, marimastat,prinostat, or metastat. In some embodiments, an additional therapy ortherapeutic agent can include recombinant interleukins, for example,aldesleukin, denileukin diftitox, interferon alfa 2a, interferon alfa2b, or peginterferon alfa 2b. In some embodiments, an additional therapyor therapeutic agent can include retinoids, for example, alitretinoin,bexarotene, or tretinoin. In some embodiments, an additional therapy ortherapeutic agent can include arsenic trioxide. In some embodiments, anadditional therapy or therapeutic agent can include asparaginase,pegaspargase. In some embodiments, an additional therapy or therapeuticcan include steroids, for example, dromostanolone propionate, megestrolacetate, nandrolone (decanoate, phenpropionate), or dexamethasone. Insome embodiments, an additional therapy or therapeutic agent can includegonadotropin releasing hormone agonists or antagonists, for example,abarelix, goserelin acetate, histrelin acetate, or leuprolide acetate.In some embodiments, an additional therapy or therapeutic agent caninclude thalidomide, lenalidomide, CC-5013, or CC-4047). In someembodiments, an additional or therapeutic agent can includemercaptopurine. In some embodiments, an additional therapy ortherapeutic agent can include mitotane. In some embodiments, anadditional therapy or therapeutic agent can include pamidronate. In someembodiments, an additional therapy or therapeutic agent can includepegademase. In some embodiments, an additional therapy or therapeuticagent can include rasburicase. In some embodiments, an additionaltherapy or therapeutic agent can include BH3 mimetics, for example,ABT-737. In some embodiments, an additional therapy or therapeutic agentcan include colony-stimulating factor analogs, for example, filgrastim,pegfilgrastim, or sargramostim. In some embodiments, an additionaltherapy or therapeutic agent can include erythropoietin or analoguesthereof (e.g. darbepoetin alfa). In some embodiments, an additionaltherapy or therapeutic agent can include interleukin 11. In someembodiments, an additional therapy or therapeutic agent can includeoprelvekin. In some embodiments, an additional therapy or therapeuticagent can include zoledronate or zoledronic acid. In some embodiments,an additional therapy or therapeutic agent can include fentanyl. In someembodiments, an additional therapy or therapeutic agent can includebisphosphonate. In some embodiments, an additional therapy ortherapeutic agent can include palifermin. In some embodiments, anadditional therapy or therapeutic agent can include a steroidalcytochrome P45017alpha-hydroxylase-17,20-lyase inhibitor (CYP17), forexample, abiraterone, or abiraterone acetate. In some embodiments, anadditional therapy or therapeutic agent can include a CDK9 inhibitor,for example, flavoperidol. In some embodiments, an additional therapy ortherapeutic agent can include anti-androgens, for example, flutamide,bicalutamide, or nilutamide. In some embodiments, an additional therapyor therapeutic agent can include luteinizing hormone-releasing hormone(LHRH) analogs, for example, leuprolide, goserelin, triptorelin, andhistrelin. In some embodiments, an additional therapy or therapeuticagent can include LHRH antagonists (e.g., degarelix), androgen receptorblockers (e.g., enzalutamide), or agents that inhibit androgenproduction (e.g., abiraterone). In some embodiments, an additionaltherapy or therapeutic agent can include an anti-viral agent, forexample, nucleoside and nucleotide reverse transcriptase inhibitors(NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs),protease inhibitors, or other antiviral drugs.

Non-limiting examples NRTIs include zidovudine (AZT); didanosine (ddl);zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir(1592U89); adefovirdipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194);BCH-10652; emitricitabine [(−)-FTC]; beta-L-FD4 (also called beta-L-D4Cand named beta-L-2′, 3′-dicleoxy-5-fluoro-cytidene); DAPD,((−)-beta-D-2,6,-diamino-purine dioxolane); and lodenosine (FddA/);nevirapine (BI-RG-587); delaviradine (BHAP, U-90152); efavirenz(DMP-266); PNU-142721; AG-1549; MKC-442(1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione);and (-t-)-calanolide A (NSC-675451) and B. Non-limiting examples ofprotease inhibitors include saquinavir (Ro 31-8959); ritonavir(ABT-538); indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94);lasinavir (BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1549.Non-limiting examples of other antiviral drugs include hydroxyurea,ribavirin, IL-2, IL-12, pentafuside and Yissum Project No. 11607. Insome embodiments, an additional therapy or therapeutic agent can includea protein chaperone inhibitor, for example an inhibitor of Hsp90 (e.g.,tanespimycin). In some embodiments, an additional therapy or therapeuticagent can include a PARP inhibitor, for example, olaparib. In someembodiments, an additional therapy or therapeutic agent can includepemetrexed. In some embodiments, an additional therapy or therapeuticagent can include an antimetabolite (e.g., folic acid antagonists,pyrimidine analogs, purine analogs and adenosine deaminase inhibitors),for example, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate,pentostatine, ara-C, ara-A, gemcitabine, orN-phosphonoacetyl-L-aspartate. In some embodiments, an additionaltherapy or therapeutic agent can include a cytotoxic agent, for example,navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafine,ifosamide, or droloxafine. In some embodiments, an additional therapy ortherapeutic agent can include a histidyl-tRNA synthetase (HRS)polypeptide or an expressible nucleotide that encodes the HRSpolypeptide. In some embodiments, an additional therapy or therapeuticagent can include erythrohydroxynonyladenine. In some embodiments, anadditional therapy or therapeutic agent can include ethinyl estradiol,fluoxymesterone, hydroxyprogesterone caproate, medroxyprogesteroneacetate, or testosterone propionate. In some embodiments, an additionaltherapy or therapeutic agent can include an inhibitor of transcription,for example, an inhibitor of a cydin-dependent kinase (e.g., dinacidib,palbocidib, olomoucine, AT7519M, P1446A-05, AG-024322, (R)-roscovitine,P276-00, SNS-032, LEE011, PD 0332991, GT28-01, NSC 638850,aminopurvalanol A, arcyriaflavin A, AZD 5438, (R)-CR8, (R)-DRF053,dihydrochloride, E9, flavopiridol, 10Z-hymenialdisine,irdirubin-3′-oxime, kenpaullone, NSC 625987, NSC 663284, NSC 693868, NU2058, NU 6140, olomoucine, PH A 767491, purvalanol A, purvalanol B, RO3306, ryuvidine, senexin A, SNS 032, SU 9516, THZ1((E)-N-(3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)phenyl)-4-(4-(dimethylamino)but-2-enamido)benzamide),THZ5-31-1((E)-N-(4-((3R)-3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)piperidine-1-carbonyl)phenyl)-4-(dimethylamino)but-2-enamide),p16 protein, p15 protein, p18 protein, p19 protein, p21/WAF1 protein,p27 protein, or p57 protein), N-(4-(2-((1s,4s)-4-(dimethylamino)cyclohexyiamino)-9-isopropyl-9H-purin-6-ylamino)phenyl)acrylamide,N-(3-(3-ethyl-5-(2-(2-hydroxyethyl)piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)phenyl)acrylamide, tert-butyl 2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6a, 7-dihydro-6H-thieno[3,2-f][1,2, 4]triazolo[4,3-a][1, 4]diazepin-6-yl)acetate, an inhibitor of abromodomain-containing protein (e.g., I-BET151, I-BET 762, JQ1, OTX-015,TEN-010, CPI-203, CPI-0610, RVX-208, LY294002, BMS-986158, GSK525762), aTBP (TATA box binding protein)-associated factor protein (TAF)inhibitor, a CREB-binding protein (CBP) inhibitor, or an E1A bindingprotein p300 (EP300) inhibitor. In some embodiments, an additionaltherapy or therapeutic agent can include a therapy for focal segmentalglomerulosclerosis, for example, any of the compounds disclosed in U.S.Patent Application Publication No. 2018/0141587, incorporated herein byreference. In some embodiments, an additional therapy or therapeuticagent can include a bile acid sequesterant, e.g., cholestyramine,colesevelam, colesevalam hydrochloride, colestipol, or selevamer. Insome embodiments, an additional therapy or therapeutic can include amast cell stabilizer, for example, cromolyn sodium. In some embodiments,an additional therapy or therapeutic agent can include a PD-1antagonist, for example, AMP-224 (B7-DClg), AMP-514, an immunoadhesinthat specifically binds to PD-1, BAP049-Clone-B, BAP049-Clone-E,h409A11, h409A16, H409A17, nivolumab (BMS-936558), PDR001, pembrolizumab(also known as MK-3475), or pidilizumab. In some embodiments, anadditional therapy or therapeutic agent can include a PD-L-1 antagonist,for example, an immunoadhesin that specifically binds to PD-L1,BMS-936559, MEDI4736, MPDL3280A, or MSB0010718C. In some embodiments, anadditional therapy or therapeutic agent can include an apoptosismodulator or a signal transduction inhibitor, for example, everolimus,perifosine, rapamycin, sorafenib, temsirolimus, trametinib, orvemurafenib.

Treatment of a subject having a cancer with a FGFR inhibitor incombination with an additional therapy or therapeutic agent including animmunomodulatory or anti-inflammatory agent can have increasedtherapeutic efficacy as compared to treatment of the same subject or asimilar subject with the FGFR inhibitor as a monotherapy. Accordingly,provided are methods of treating a subject in need thereof includingadministering to the subject a compound of Formula I an additionaltherapy or therapeutic agent comprising an immunomodulatory oranti-inflammatory agent.

Exemplary immunomodulatory or anti-inflammatory agents include, withoutlimitation, cyclosporin, rapamycin, or ascomycin, or immunosuppressantanalogues thereof, for example, cyclosporin A (CsA), cyclosporin G,FK-506, rapamycin, or comparable compounds, corticosteroids,cyclophosphamide, azathioprine, methotrexate, brequinar, leflunomide,mizoribine, mycophenolic acid, mycophenolate mofetil,15-deoxyspergualin, immunosuppressant antibodies, such as monoclonalantibodies for leukocyte receptors, for example MHC, CD2, CD3, CD4, CD7,CD25, CD28, B7, CD45, CD58 or their ligands, or other immunomodulatorycompounds, such as CTLA41g.

Treatment of a subject having a cancer with a FGFR inhibitor incombination with an additional therapy or therapeutic agent including aninhibitor of the interaction between a FGFR and FGFR substrate 2 (FRS2)can have increased therapeutic efficacy as compared to treatment of thesame subject or a similar subject with the FGFR inhibitor as amonotherapy. Accordingly, provided are methods of treating a subject inneed thereof including administering to the subject a compound ofFormula I an additional therapy or therapeutic agent comprisinginhibitor of the interaction between a FGFR and FRS2.

Non-limiting exemplary inhibitors of the interaction between a FGFR andFRS2 are described in U.S. Pat. No. 9,957,236, incorporated herein byreference.

In some embodiments, the other FGFR-targeted therapeutic is amultikinase inhibitor exhibiting FGFR inhibition activity. In someembodiments, the other FGFR-targeted therapeutic inhibitor is selectivefor a FGFR kinase. Exemplary FGFR kinase inhibitors can exhibitinhibition activity (IC₅₀) against a FGFR kinase of less than about 1000nM, less than about 500 nM, less than about 200 nM, less than about 100nM, less than about 50 nM, less than about 25 nM, less than about 10 nM,or less than about 1 nM as measured in an assay as described herein. Insome embodiments, a FGFR kinase inhibitors can exhibit inhibitionactivity (IC₅₀) against a FGFR kinase of less than about 25 nM, lessthan about 10 nM, less than about 5 nM, or less than about 1 nM asmeasured in an assay as provided herein.

Non-limiting examples of FGFR-targeted therapeutics (e.g., a first FGFRinhibitor or a second FGFR inhibitor) include masitinib(AB1010,4-[(4-methylpiperazin-1-yl)methyl]-N-[4-methyl-3-[(4-pyridin-3-yl-1,3-thiazol-2-yl)amino]phenyl]benzamide),EOC317 (ACTB1003,l-[4-[4-amino-6-(methoxymethyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl]-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea),Anlotinib (AL3818,l-[[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinolin-7-yl]oxymethyl]cyclopropan-1-amine),Ponatinib(AP24535,3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]benzamide),Regorafenib (BAY73-4506,4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide),Rogaratinib(BAY1163877,4-[[4-amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl]piperazin-2-one),Dasatinib (BMS 354825,N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-1,3-thiazole-5-carboxamide),Brivanib (BMS-540215,(2R)-1-[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]oxypropan-2-ol),Debio 1347 (CH5183284,(5-amino-1-(2-methyl-1H-benzo[d]imidazol-6-yl)-1H-pyrazol-4-yl)(1H-indol-2-yl)methanone),ARQ-087 (derazantinib,(6R)-6-(2-fluorophenyl)-N-[3-[2-(2-methoxyethylamino)ethyl]phenyl]-5,6-dihydrobenzo[h]quinazolin-2-amine),Lucitanib(E3810,6-[7-[(1-aminocyclopropyl)methoxy]-6-methoxyquinolin-4-yl]oxy-N-methylnaphthalene-1-carboxamide),Lenvatinib (E-7080, Lenvima®,4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxyquinoline-6-carboxamide),Erdafitinib (JNJ42756493,N′-(3,5-dimethoxyphenyl)-N′-[3-(1-methylpyrazol-4-yl)quinoxalin-6-yl]-N-propan-2-ylethane-1,2-diamine),BIBF1120 (nintedanib, methyl(3Z)-3-[[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]anilino]-phenylmethylidene]-2-oxo-1H-indole-6-carboxylate),BGJ398 (NVP-BGJ398, infigratinib,3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-[6-[4-(4-ethylpiperazin-1-yl)anilino]pyrimidin-4-yl]-1-methylurea),nintedanib (Ofev®, Vargatef®, Methyl(3Z)-3-{[(4-{methyl[(4-methylpiperazin-1-yl)acetyl]amino}phenyl)amino](phenyl)methylidene}-2-oxo-2,3-dihydro-1H-indole-6-carboxylate),Dovitinib (TKI258, CHIR 258,(3Z)-4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1,3-dihydrobenzimidazol-2-ylidene]quinolin-2-one),Orantinib(TSU-68,3-[2,4-dimethyl-5-[(Z)-(2-oxo-1H-indol-3-ylidene)methyl]-1H-pyrrol-3-yl]propanoicacid), ASP5878(2-(4-((5-((2,6-difluoro-3,5-dimethoxybenzyl)oxy)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)ethan-1-ol),TAS-120(1-[(3S)-3-[4-amino-3-[2-(3,5-dimethoxyphenyl)ethynyl]pyrazolo[3,4-d]pyrimidin-1-yl]pyrrolidin-1-yl]prop-2-en-1-one),pazopanib(5-[[4-[(2,3-dimethylindazol-6-yl)-methylamino]pyrimidin-2-yl]amino]-2-methylbenzenesulfonamide),pemigatinib(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-4,7-dihydropyrrolo[4,5]pyrido[1,2-d]pyrimidin-2-one),E7090(5-[2-[[4-[1-(2-hydroxyethyl)piperidin-4-yl]benzoyl]amino]pyridin-4-yl]oxy-6-(2-methoxyethoxy)-N-methylindole-1-carboxamide),PRN1371(6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-8-[3-(4-prop-2-enoylpiperazin-1-yl)propyl]pyrido[2,3-d]pyrimidin-7-one),BLU-554(N-[(3S,4S)-3-[[6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl]amino]oxan-4-yl]prop-2-enamide),Sulfatinib(N-[2-(dimethylamino)ethyl]-1-[3-[[4-[(2-methyl-1H-indol-5-yl)oxy]pyrimidin-2-yl]amino]phenyl]methanesulfonamide),H3B-6527(N-[2-[[6-[(2,6-dichloro-3,5-dimethoxyphenyl)carbamoyl-methylamino]pyrimidin-4-yl]amino]-5-(4-ethylpiperazin-1-yl)phenyl]prop-2-enamide),AZD4547(N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(3,5-diemthylpiperazin-1-yl)benzamide),FGF401(N-[5-cyano-4-(2-methoxyethylamino)pyridin-2-yl]-7-formyl-6-[(4-methyl-2-oxopiperazin-1-yl)methyl]-3,4-dihydro-2H-1,8-naphthyridine-1-carboxamide),XL228, HMPL-453, INCB054828, MAX-40279, XL999, INCB062079, B-701,BAY1179470, FPA144 (Bemarituzumab), BAY1187982, ISIS-FGFR4RX, andLY3076226.

Additional FGFR-targeted agents include those described in U.S. Pat.Nos. 9,931,401 and 9,925,240; U.S. Patent Application Publication Nos.2018/0237424, 2018/0194844, 2018/0161327, 2018/0155340, 2018/0065960;and PCT Publication Nos. 2018/149382 and 2018/049781, each of which isherein incorporated by reference.

Non-limiting examples of receptor tyrosine kinase (e.g., Trk) targetedtherapeutic agents include afatinib, cabozantinib, cetuximab,crizotinib, dabrafenib, entrectinib, erlotinib, gefitinib, imatinib,lapatinib, lestaurtinib, nilotinib, pazopanib, panitumumab, pertuzumab,sunitinib, trastuzumab,I-((3S,4R)-4-(3-fluorophenyl)-I-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-methylpyrimidin-5-yl)-I-phenyl-IH-pyrazol-5-yl)urea,AG 879, AR-772, AR-786, AR-256, AR-618, AZ-23, AZ623, DS-6051, Gö6976,GNF-5837, GTx-186, GW 441756, LOXO-101, MGCD516, PLX7486, RXDX101,VM-902A, TPX-0005, and TSR-011. Additional Trk targeted therapeuticagents include those described in U.S. Pat. Nos. 8,450,322; 8,513,263;8,933,084; 8,791,123; 8,946,226; 8,450,322; 8,299,057; and 8,912,194;U.S. Publication No. 2016/0137654; 2015/0166564; 2015/0051222;2015/0283132; and 2015/0306086; International Publication No. WO2010/033941; WO 2010/048314; WO 2016/077841; WO 2011/146336; WO2011/006074; WO 2010/033941; WO 2012/158413; WO 2014078454; WO2014078417; WO 2014078408; WO 2014078378; WO 2014078372; WO 2014078331;WO 2014078328; WO 2014078325; WO 2014078323; WO 2014078322; WO2015175788; WO 2009/013126; WO 2013/174876; WO 2015/124697; WO2010/058006; WO 2015/017533; WO 2015/112806; WO 2013/183578; and WO2013/074518, all of which are hereby incorporated by reference in theirentireties.

Further examples of Trk inhibitors can be found in U.S. Pat. No.8,637,516, International Publication No. WO 2012/034091, U.S. Pat. No.9,102,671, International Publication No. WO 2012/116217, U.S.Publication No. 2010/0297115, International Publication No. WO2009/053442, U.S. Pat. No. 8,642,035, International Publication No. WO2009092049, U.S. Pat. No. 8,691,221, International Publication No.WO2006131952, all of which are incorporated by reference in theirentireties herein. Exemplary Trk inhibitors include GNF-4256, describedin Cancer Chemother. Pharmacol. 75(1):131-141,2015; and GNF-5837(N-[3-[[2,3-dihydro-2-oxo-3-(1H-pyrrol-2-ylmethylene)-1H-indol-6-yl]amino]-4-methylphenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]-urea),described in ACS Med. Chem. Lett. 3(2):140-145,2012, each of which isincorporated by reference in its entirety herein.

Additional examples of Trk inhibitors include those disclosed in U.S.Publication No. 2010/0152219, U.S. Pat. No. 8,114,989, and InternationalPublication No. WO 2006/123113, all of which are incorporated byreference in their entireties herein. Exemplary Trk inhibitors includeAZ623, described in Cancer 117(6):1321-1391,2011; AZD6918, described inCancer Biol. Ther. 16(3):477-483,2015; AZ64, described in CancerChemother. Pharmacol. 70:477-486,2012; AZ-23((S)-5-Chloro-N2-(1-(5-fluoropyridin-2-yl)ethyl)-N4-(5-isopropoxy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine),described in Mol. Cancer Ther. 8:1818-1827,2009; and AZD7451; each ofwhich is incorporated by reference in its entirety.

A Trk inhibitor can include those described in U.S. Pat. Nos. 7,615,383;7,384,632; 6,153,189; 6,027,927; 6,025,166; 5,910,574; 5,877,016; and5,844,092, each of which is incorporated by reference in its entirety.

Further examples of Trk inhibitors include CEP-751, described in Int. J.Cancer 72:672-679,1997; CT327, described in Acta Derm. Venereol.95:542-548,2015; compounds described in International Publication No. WO2012/034095; compounds described in U.S. Pat. No. 8,673,347 andInternational Publication No. WO 2007/022999; compounds described inU.S. Pat. No. 8,338,417; compounds described in InternationalPublication No. WO 2016/027754; compounds described in U.S. Pat. No.9,242,977; compounds described in U.S. Publication No. 2016/0000783;sunitinib(N-(2-diethylaminoethyl)-5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide),as described in PLoS One 9:e95628,2014; compounds described inInternational Publication No. WO 2011/133637; compounds described inU.S. Pat. No. 8,637,256; compounds described in Expert. Opin. Ther. Pat.24(7):731-744,2014; compounds described in Expert Opin. Ther. Pat.19(3):305-319,2009; (R)-2-phenylpyrrolidine substitutedimidazopyridazines, e.g., GNF-8625,(R)-1-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-[2,4′-bipyridin]-2′-yl)piperidin-4-olas described in ACS Med. Chem. Lett. 6(5):562-567,2015; GTx-186 andothers, as described in PLoS One 8(12):e83380,2013; K252a((9S-(9α,10β,12α))-2,3,9,10,11,12-hexahydro-10-hydroxy-10-(methoxycarbonyl)-9-methyl-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i][1,6]benzodiazocin-1-one),as described in Mol. Cell Biochem. 339(1-2):201-213, 2010;4-aminopyrazolylpyrimidines, e.g., AZ-23(((S)-5-chloro-N2-(1-(5-fluoropyridin-2-yl)ethyl)-N4-(5-isopropoxy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine)),as described in J. Med. Chem. 51(15):4672-4684,2008; PHA-739358(danusertib), as described in Mol. Cancer Ther. 6:3158, 2007; Gö 6976(5,6,7,13-tetrahydro-13-methyl-5-oxo-12H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-12-propanenitrile),as described in J. Neurochem. 72:919-924,1999; GW441756((3Z)-3-[(1-methylindol-3-yl)methylidene]-1H-pyrrolo[3,2-b]pyridin-2-one),as described in UAE 115:117, 2010; milcidib (PHA-848125AC), described inJ. Carcinog. 12:22, 2013; AG-879(2E)-3-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-cyano-2-propenethioamide);altiratinib(N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide);cabozantinib(N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide);lestaurtinib((5S,6S,8R)-6-Hydroxy-6-(hydroxymethyl)-5-methyl-7,8,14,15-tetrahydro-5H-16-oxa-4b,8a,14-triaza-5,8-methanodibenzo[b,h]cycloocta[jkl]cyclopenta[e]-as-indacen-13(6H)-one);dovitinib(4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-onemono 2-hydroxypropanoate hydrate); sitravatinib(N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide);ONO-5390556; regorafenib(4-[4-({[4-Chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamidehydrate); and VSR-902A; all of the references above are incorporated byreference in their entireties herein.

The ability of a Trk inhibitor to act as a TrkA, TrkB, and/or TrkCinhibitor may be tested using the assays described in Examples A and Bin U.S. Pat. No. 8,513,263, which is incorporated herein by reference.

In some embodiments, the receptor tyrosine kinase inhibitor is anepidermal growth factor receptor typrosine kinase inhibitor (EGFR). Forexample, EGFR inhibitors can include osimertinib (merelectinib,Tagrisso), erlotinib (Tarceva), gefitinib (Iressa), cetuximab (Erbitux),necitumumab (Portrazza), neratinib (Nerlynx), lapatinib (Tykerb),panitumumab (Vectibix), and vandetanib (Caprelsa). In some embodiments,the EGFR inhibitor is osimertinib.

In some embodiments, signal transduction pathway inhibitors includeRas-Raf-MEK-ERK pathway inhibitors (e.g., binimetinib, selumetinib,encorafenib, sorafenib, trametinib, and vemurafenib), PI3K-Akt-mTOR-S6Kpathway inhibitors (e.g. everolimus, rapamycin, perifosine,temsirolimus), JAK-STAT pathway inhibitors (e.g., methotrexate,ruxolitinib, tofacitinib, odacitinib, baricitinib) and other kinaseinhibitors, such as baricitinib, brigatinib, capmatinib, danusertib,ibrutinib, milcidib, quercetin, regorafenib, ruxolitinib, semaxanib,AP32788, BLU285, BLU554, INCB39110, INCB40093, INCB50465, INCB52793,INCB54828, MGCD265, NMS-088, NMS-1286937, PF 477736((R)-amino-N-[5,6-dihydro-2-(1-methyl-1H-pyrazol-4-yl)-6-oxo-1Hpyrrolo[4,3,2-ef][2,3]benzodiazepin-8-yl]-cyclohexaneacetamide),PLX3397, PLX7486, PLX8394, PLX9486, PRN1008, PRN1371, RXDX103, RXDX106,RXDX108, and TG101209(N-tert-butyl-3-(5-methyl-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)benzenesulfonamide).

Non-limiting examples of checkpoint inhibitors include ipilimumab,tremelimumab, nivolumab, pidilizumab, MPDL3208A, MEDI4736, MSB0010718C,BMS-936559, BMS-935559 (MDX-1105), AMP-224, and pembrolizumab.

In some embodiments, cytotoxic chemotherapeutics are selected fromarsenic trioxide, bleomycin, cabazitaxel, capecitabine, carboplatin,cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin,docetaxel, doxorubicin, etoposide, fluorouracil, gemcitabine,irinotecan, lomustine, methotrexate, mitomycin C, oxaliplatin,paditaxel, pemetrexed, temozolomide, and vincristine.

Non-limiting examples of angiogenesis-targeted therapies includeaflibercept and bevacizumab.

The term “immunotherapy” refers to an agent that modulates the immunesystem. In some embodiments, an immunotherapy can increase theexpression and/or activity of a regulator of the immune system. In someembodiments, an immunotherapy can decrease the expression and/oractivity of a regulator of the immune system. In some embodiments, animmunotherapy can recruit and/or enhance the activity of an immune cell.

In some embodiments, the immunotherapy is a cellular immunotherapy(e.g., adoptive T-cell therapy, dendritic cell therapy, natural killercell therapy). In some embodiments, the cellular immunotherapy issipuleucel-T (APC8015; Provenge™; Plosker (2011) Drugs 71(1): 101-108).In some embodiments, the cellular immunotherapy includes cells thatexpress a chimeric antigen receptor (CAR). In some embodiments, thecellular immunotherapy is a CAR-T cell therapy. In some embodiments, theCAR-T cell therapy is tisagenledeucel (Kymriah™).

In some embodiments, the immunotherapy is an antibody therapy (e.g., amonoclonal antibody, a conjugated antibody). In some embodiments, theantibody therapy is bevacizumab (Mvasti™, Avastin®), trastuzumab(Herceptin®), avelumab (Bavencio®), rituximab (MabThera™, Rituxan®),edrecolomab (Panorex), daratumuab (Darzalex®), olaratumab (Lartruvo™),ofatumumab (Arzerra®), alemtuzumab (Campath®), cetuximab (Erbitux®),oregovomab, pembrolizumab (Keytruda®), dinutiximab (Unituxin®),obinutuzumab (Gazyva®), tremelimumab (CP-675,206), ramucirumab(Cyramza®), ublituximab (TG-1101), panitumumab (Vectibix®), elotuzumab(Empliciti™), avelumab (Bavencio®), necitumumab (Portrazza™),cirmtuzumab (UC-961), ibritumomab (Zevalin®), isatuximab (SAR650984),nimotuzumab, fresolimumab (GC1008), lirilumab (INN), mogamulizumab(Poteligeo®), ficlatuzumab (AV-299), denosumab (Xgeva®), ganitumab,urelumab, pidilizumab or amatuximab.

In some embodiments, the immunotherapy is an antibody-drug conjugate. Insome embodiments, the antibody-drug conjugate is gemtuzumab ozogamicin(Mytotarg™), inotuzumab ozogamicin (Besponsa®), brentuximab vedotin(Adcetris®), ado-trastuzumab emtansine (TDM-1; Kadcyla®), mirvetuximabsoravtansine (IMGN853) or anetumab ravtansine.

In some embodiments, the immunotherapy includes blinatumomab (AMG103;Blincyto®) or midostaurin (Rydapt).

In some embodiments, the immunotherapy includes a toxin. In someembodiments, the immunotherapy is denileukin diftitox (Ontak®).

In some embodiments, the immunotherapy is a cytokine therapy. In someembodiments, the cytokine therapy is an interleukin 2 (IL-2) therapy, aninterferon alpha (IFNα) therapy, a granulocyte colony stimulating factor(G-CSF) therapy, an interleukin 12 (IL-12) therapy, an interleukin 15(IL-15) therapy, an interleukin 7 (IL-7) therapy or anerythropoietin-alpha (EPO) therapy. In some embodiments, the IL-2therapy is aldesleukin (Proleukin®). In some embodiments, the IFNαtherapy is IntronA® (Roferon-A®). In some embodiments, the G-CSF therapyis filgrastim (Neupogen®).

In some embodiments, the immunotherapy is an immune checkpointinhibitor. In some embodiments, the immunotherapy includes one or moreimmune checkpoint inhibitors. In some embodiments, the immune checkpointinhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor or a PD-L1 inhibitor.In some embodiments, the CTLA-4 inhibitor is ipilimumab (Yervoy®) ortremelimumab (CP-675,206). In some embodiments, the PD-1 inhibitor ispembrolizumab (Keytruda®) or nivolumab (Opdivo®). In some embodiments,the PD-L1 inhibitor is atezolizumab (Tecentriq®), avelumab (Bavencio®)or durvalumab (Imfinzi™).

In some embodiments, the immunotherapy is mRNA-based immunotherapy. Insome embodiments, the mRNA-based immunotherapy is CV9104 (see, e.g.,Rausch et al. (2014) Human Vaccin Immunother 10(11): 3146-52; and Kubleret al. (2015) J. Immunother Cancer 3:26).

In some embodiments, the immunotherapy is bacillus Calmette-Guerin (BCG)therapy.

In some embodiments, the immunotherapy is an oncolytic virus therapy. Insome embodiments, the oncolytic virus therapy is talimogenealherparepvec (T-VEC; Imlygic®).

In some embodiments, the immunotherapy is a cancer vaccine. In someembodiments, the cancer vaccine is a human papillomavirus (HPV) vaccine.In some embodiments, the HPV vaccine is Gardasil®, Gardasil9® orCervarix®. In some embodiments, the cancer vaccine is a hepatitis Bvirus (HBV) vaccine. In some embodiments, the HBV vaccine is Engerix-B®,Recombivax HB® or GI-13020 (Tarmogen®). In some embodiments, the cancervaccine is Twinrix® or Pediarix®. In some embodiments, the cancervaccine is BiovaxlD® Oncophage® GVAX, ADXS11-001, ALVAC-CEA, PROSTVAC®Rindopepimut® CimaVax-EGF, lapuleucel-T (APC8024; Neuvenge™), GRNVAC1,GRNVAC2, GRN-1201, hepcortespenlisimut-L (Hepko-V5), DCVAX® SCIB1, BMTCTN 1401, PrCa VBIR, PAN VAC, ProstAtak® DPX-Survivac, orviagenpumatucel-L (HS-110).

In some embodiments, the immunotherapy is a peptide vaccine. In someembodiments, the peptide vaccine is nelipepimut-S (E75) (NeuVax™),IMA901, or SurVaxM (SVN53-67). In some embodiments, the cancer vaccineis an immunogenic personal neoantigen vaccine (see, e.g., Ott et al.(2017) Nature 547:217-221; Sahin et al. (2017) Nature 547:222-226). Insome embodiments, the cancer vaccine is RGSH4K, or NEO-PV-01. In someembodiments, the cancer vaccine is a DNA-based vaccine. In someembodiments, the DNA-based vaccine is a mammaglobin-A DNA vaccine (see,e.g., Kim et al. (2016) Oncolmmunology 5(2): el069940).

In some embodiments, immune-targeted agents are selected fromaldesleukin, interferon alfa-2b, ipilimumab, lambrolizumab, nivolumab,prednisone, and sipuleucel-T.

Non-limiting examples of radiotherapy include radioiodide therapy,external-beam radiation, and radium 223 therapy.

Additional kinase inhibitors include those described in, for example,U.S. Pat. Nos. 7,514,446; 7,863,289; 8,026,247; 8,501,756; 8,552,002;8,815,901; 8,912,204; 9,260,437; 9,273,051; U.S. Publication No. US2015/0018336; International Publication No. WO 2007/002325; WO2007/002433; WO 2008/080001; WO 2008/079906; WO 2008/079903; WO2008/079909; WO 2008/080015; WO 2009/007748; WO 2009/012283; WO2009/143018; WO 2009/143024; WO 2009/014637; 2009/152083; WO2010/111527; WO 2012/109075; WO 2014/194127; WO 2015/112806; WO2007/110344; WO 2009/071480; WO 2009/118411; WO 2010/031816; WO2010/145998; WO 2011/092120; WO 2012/101032; WO 2012/139930; WO2012/143248; WO 2012/152763; WO 2013/014039; WO 2013/102059; WO2013/050448; WO 2013/050446; WO 2014/019908; WO 2014/072220; WO2014/184069; and WO 2016/075224 all of which are hereby incorporated byreference in their entireties.

Further examples of kinase inhibitors include those described in, forexample, WO 2016/081450; WO 2016/022569; WO 2016/011141; WO 2016/011144;WO 2016/011147; WO 2015/191667; WO 2012/101029; WO 2012/113774; WO2015/191666; WO 2015/161277; WO 2015/161274; WO 2015/108992; WO2015/061572; WO 2015/058129; WO 2015/057873; WO 2015/017528;WO/2015/017533; WO 2014/160521; and WO 2014/011900, each of which ishereby incorporated by reference in its entirety.

Further examples of kinase inhibitors include luminespib (AUY-922,NVP-AUY922)(5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-4-(4-(morpholinomethyl)phenyl)isoxazole-3-carboxamide)and doramapimod (BIRB-796)(1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea).

Accordingly, also provided herein is a method of treating cancer,comprising administering to a subject in need thereof a pharmaceuticalcombination for treating cancer which comprises (a) a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof, (b)an additional therapeutic agent, and (c) optionally at least onepharmaceutically acceptable carrier for simultaneous, separate orsequential use for the treatment of cancer, wherein the amounts of thecompound of Formula I or a pharmaceutically acceptable salt or solvatethereof and the additional therapeutic agent are together effective intreating the cancer.

These additional therapeutic agents may be administered with one or moredoses of the compound of Formula I, or a pharmaceutically acceptablesalt or solvate thereof, or pharmaceutical composition thereof, as partof the same or separate dosage forms, via the same or different routesof administration, and/or on the same or different administrationschedules according to standard pharmaceutical practice known to oneskilled in the art.

In some embodiments of any of the methods disclosed herein, theadditional therapeutic agent(s) includes any one of the above listedtherapies or therapeutic agents which are standards of care in cancerswherein the cancer has a dysregulation of a FGFR gene, a FGFR protein,or expression or activity, or level of any of the same.

Also provided herein is (i) a pharmaceutical combination for treating acancer in a subject in need thereof, which comprises (a) a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof, (b)at least one additional therapeutic agent (e.g., any of the exemplaryadditional therapeutic agents described herein or known in the art), and(c) optionally at least one pharmaceutically acceptable carrier forsimultaneous, separate or sequential use for the treatment of cancer,wherein the amounts of the compound of Formula I or pharmaceuticallyacceptable salt or solvate thereof and of the additional therapeuticagent are together effective in treating the cancer; (ii) apharmaceutical composition comprising such a combination; (iii) the useof such a combination for the preparation of a medicament for thetreatment of cancer; and (iv) a commercial package or product comprisingsuch a combination as a combined preparation for simultaneous, separateor sequential use; and to a method of treatment of cancer in a subjectin need thereof. In some embodiments, the subject is a human. In someembodiments, the cancer is a FGFR-associated cancer. For example, aFGFR-associated cancer having one or more FGFR inhibitor resistancemutations.

The term “pharmaceutical combination”, as used herein, refers to apharmaceutical therapy resulting from the mixing or combining of morethan one active ingredient and includes both fixed and non-fixedcombinations of the active ingredients. The term “fixed combination”means that a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and at least one additional therapeutic agent (e.g.,a chemotherapeutic agent), are both administered to a subjectsimultaneously in the form of a single composition or dosage. The term“non-fixed combination” means that a compound of Formula I or apharmaceutically acceptable salt or solvate thereof and at least oneadditional therapeutic agent (e.g., chemotherapeutic agent) areformulated as separate compositions or dosages such that they may beadministered to a subject in need thereof simultaneously, concurrentlyor sequentially with variable intervening time limits, wherein suchadministration provides effective levels of the two or more compounds inthe body of the subject. These also apply to cocktail therapies, e.g.the administration of three or more active ingredients.

Accordingly, also provided herein is a method of treating a disease ordisorder, comprising administering to a subject in need thereof apharmaceutical combination for treating the disease or disorder whichcomprises (a) a compound of Formula I or pharmaceutically acceptablesalt or solvate thereof, (b) an additional therapeutic agent, and (c)optionally at least one pharmaceutically acceptable carrier forsimultaneous, separate or sequential use for the treatment of thedisease or disorder, wherein the amounts of the compound of Formula I orpharmaceutically acceptable salt or solvate thereof and the additionaltherapeutic agent are together effective in treating the disease ordisorder. In some embodiments, the compound of Formula I orpharmaceutically acceptable salt or solvate thereof, and the additionaltherapeutic agent are administered simultaneously as separate dosages.In some embodiments, the compound of Formula I or pharmaceuticallyacceptable salt or solvate thereof, and the additional therapeutic agentare administered as separate dosages sequentially in any order, injointly therapeutically effective amounts, e.g. in daily orintermittently dosages. In some embodiments, the compound of Formula Ior pharmaceutically acceptable salt or solvate thereof, and theadditional therapeutic agent are administered simultaneously as acombined dosage. In some embodiments, the disease or disorder is aFGFR-associated disease or disorder. In some embodiments, the subjecthas been administered one or more doses of a compound of Formula I, or apharmaceutically acceptable salt thereof, prior to administration of thepharmaceutical composition.

Also provided herein is a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof, for use in the treatment of aFGFR-associated disease or disorder as defined hereinabove.

In certain embodiments of these methods, the treatment period can befrom about 1 day to about 30 days (e.g., from about 1 day to about 15days; e.g. about 7 days; e.g., from about 16 days to about 30 days,e.g., about 21 days). In other embodiments of these methods, thetreatment period can be from 30 days to about 12 months (e.g., fromabout 30 days to about 9 months, from about 30 days to about 6 months,from about 30 days to about 120 days, from about 30 days to about 90days, from about 30 days to about 60 days). In still other embodiments,the treatment period is 7 days or more or 21 days or more (e.g., morethan 7 days or more than 21 days to about 12 months, more than 7 days ormore than 21 days to about 9 months, more than 7 days or more than 21days to about 6 months, more than 7 days or more than 21 days to about120 days, more than 7 days or more than 21 days to about 90 days, morethan 7 days or more than 21 days to about 60 days, more than 7 days ormore than 21 days to about 30 days).

In some embodiments of these methods, the treatment period is at leastor about 1 day, at least or about 2 days, at least or about 3 days, atleast or about 4 days, at least or about 5 days, at least or about 6days, at least or about 7 days, at least or about 8 days, at least orabout 9 days, at least or about 10 days, at least or about 11 days, atleast or about 12 days, at least or about 13 days, at least or about 14days, at least or about 15 days, at least or about 16 days, at least orabout 17 days, at least or about 18 days, at least or about 19 days, atleast or about 20 days, at least or about 21 days, at least or about 22days, at least or about 23 days, at least or about 24 days, at least orabout 25 days, at least or about 26 days, at least or about 27 days, atleast or about 28 days, at least or about 29 days, at least or about 30days, at least or about 31 days, at least or about 45 days, at least orabout 60 days, at least or about 90 days, at least or about 120 days, atleast or about 6 months, at least or about 9 months, at least or about12 months.

Accordingly, also provided herein is a method of treating a cancer,comprising administering to a subject in need thereof a pharmaceuticalcombination for treating cancer which comprises (a) a compound ofFormula I or pharmaceutically acceptable salt or solvate thereof, (b) anadditional therapeutic agent, and (c) optionally at least onepharmaceutically acceptable carrier for simultaneous, separate orsequential use for the treatment of cancer, wherein the amounts of thecompound of Formula I or pharmaceutically acceptable salt or solvatethereof and the additional therapeutic agent are together effective intreating the cancer. In some embodiments, the compound of Formula I orpharmaceutically acceptable salt or solvate thereof, and the additionaltherapeutic agent are administered simultaneously as separate dosages.In some embodiments, the compound of Formula I or pharmaceuticallyacceptable salt or solvate thereof, and the additional therapeutic agentare administered as separate dosages sequentially in any order, injointly therapeutically effective amounts, e.g. in daily orintermittently dosages. In some embodiments, the compound of Formula Ior pharmaceutically acceptable salt or solvate thereof, and theadditional therapeutic agent are administered simultaneously as acombined dosage. In some embodiments, the cancer is a FGFR-associatedcancer. For example, a FGFR-associated cancer having one or more FGFRinhibitor resistance mutations. In some embodiments, the additionaltherapeutic agent is crizotinib. In some embodiments, the additionaltherapeutic agent is osimertinib. In some embodiments, the subject hasbeen administered one or more doses of a compound of Formula I, or apharmaceutically acceptable salt thereof, prior to administration of thepharmaceutical composition. In some embodiments, the cancer is a bladdercancer (e.g., a FGFR-associated bladder cancer).

Also provided herein is a method of treating a disease or disordermediated by FGFR in a subject in need of such treatment, the methodcomprising administering to the subject a therapeutically effectiveamount of a compound of Formula I or pharmaceutically acceptable salt orsolvate thereof. In some embodiments, the disease or disorder mediatedby FGFR is a dysregulation of FGFR gene, a FGFR kinase, or expression oractivity or level of any of the same. For example, the dysregulation ofa FGFR gene, a FGFR kinase, or expression or activity or level of any ofthe same includes one or more FGFR inhibitor resistance mutations. Adisease or disorder mediated by FGFR can include any disease, disorderor condition that is directly or indirectly linked to expression oractivity of a FGFR, including overexpression and/or abnormal activitylevels. In some embodiments, the disease is cancer (e.g., aFGFR-associated cancer). In some embodiments, the cancer is any of thecancers or FGFR-associated cancers described herein. In someembodiments, the additional therapeutic agent is crizotinib. In someembodiments, the additional therapeutic agent is osimertinib. In someembodiments, the subject has been administered one or more doses of acompound of Formula I, or a pharmaceutically acceptable salt thereof,prior to administration of the pharmaceutical composition. In someembodiments, the cancer is a bladder cancer (e.g., a FGFR-associatedbladder cancer).

Although the genetic basis of tumorigenesis may vary between differentcancer types, the cellular and molecular mechanisms required formetastasis appear to be similar for all solid tumor types. During ametastatic cascade, the cancer cells lose growth inhibitory responses,undergo alterations in adhesiveness and produce enzymes that can degradeextracellular matrix components. This leads to detachment of tumor cellsfrom the original tumor, infiltration into the circulation through newlyformed vasculature, migration and extravasation of the tumor cells atfavorable distant sites where they may form colonies. A number of geneshave been identified as being promoters or suppressors of metastasis.FGFR proteins have been implicated for a role in metastasis (Qian etal., Oncogene 33:3411-3421,2014).

Accordingly, also provided herein are methods for inhibiting,preventing, aiding in the prevention, or decreasing the symptoms ofmetastasis of a cancer in a subject in need thereof, the methodcomprising administering to the subject a therapeutically effectiveamount of a compound of Formula I or pharmaceutically acceptable salt orsolvate thereof. Such methods can be used in the treatment of one ormore of the cancers described herein. See, e.g., US Publication No.2013/0029925; International Publication No. WO 2014/083567; and U.S.Pat. No. 8,568,998. See also, e.g., Hezam K et al., Rev Neurosci 2018Jan. 26; 29:93-98; Gao L, et al., Pancreas 2015 January; 44:134-143;Ding K et al., J Biol Chem 2014 Jun. 6; 289:16057-71; and Amit M et al.,Oncogene 2017 Jun. 8; 36:3232-3239. In some embodiments, the cancer is aFGFR-associated cancer. In some embodiments, the compound of Formula Ior a pharmaceutically acceptable salt or solvate thereof is used incombination with an additional therapy or another therapeutic agent,including a chemotherapeutic agent, such as a kinase inhibitor. Forexample, a first or second FGFR kinase inhibitor. In some embodiments,the additional therapeutic agent is crizotinib. In some embodiments, theadditional therapeutic agent is osimertinib. In some embodiments, thesubject has been administered one or more doses of a compound of FormulaI, or a pharmaceutically acceptable salt thereof, prior toadministration of the pharmaceutical composition. In some embodiments,the cancer is a bladder cancer (e.g., a FGFR-associated bladder cancer).

The term “metastasis” is an art known term and means the formation of anadditional tumor (e.g., a solid tumor) at a site distant from a primarytumor in a subject or patient, where the additional tumor includes thesame or similar cancer cells as the primary tumor.

Also provided are methods of decreasing the risk of developing ametastasis or an additional metastasis in a subject having aFGFR-associated cancer that include: selecting, identifying, ordiagnosing a subject as having a FGFR-associated cancer, andadministering a therapeutically effective amount of a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof tothe subject selected, identified, or diagnosed as having aFGFR-associated cancer. Also provided are methods of decreasing the riskof developing a metastasis or an additional metastasis in a subjecthaving a FGFR-associated cancer that includes administering atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt or solvent thereof to a subject havinga FGFR-associated cancer. The decrease in the risk of developing ametastasis or an additional metastasis in a subject having aFGFR-associated cancer can be compared to the risk of developing ametastasis or an additional metastasis in the subject prior totreatment, or as compared to a subject or a population of subjectshaving a similar or the same FGFR-associated cancer that has received notreatment or a different treatment. The decrease in the risk ofdeveloping a metastasis or an additional metastasis can be about 1% toabout 99%, about 95%, about 90%, about 85%, about 80%, about 75%, about70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%,about 35%, about 30%, about 25%, about 20%, about 15%, about 10%, orabout 5%; about 5% to about 99%, about 95%, about 90%, about 85%, about80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%,about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about15%, or about 10%; about 10% to about 99%, about 95%, about 90%, about85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%,about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about20%, or about 15%; about 15% to about 99%, about 95%, about 90%, about85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%,about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, orabout 20%; about 20% to about 99%, about 95%, about 90%, about 85%,about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about50%, about 45%, about 40%, about 35%, about 30%, or about 25%; about 25%to about 99%, about 95%, about 90%, about 85%, about 80%, about 75%,about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about40%, about 35%, or about 30%; about 30% to about 99%, about 95%, about90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%,about 55%, about 50%, about 45%, about 40%, or about 35%; about 35% toabout 99%, about 95%, about 90%, about 85%, about 80%, about 75%, about70%, about 65%, about 60%, about 55%, about 50%, about 45%, or about40%; about 40% to about 99%, about 95%, about 90%, about 85%, about 80%,about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, orabout 45%; about 45% to about 99%, about 95%, about 90%, about 85%,about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, orabout 50%; about 50% to about 99%, about 95%, about 90%, about 85%,about 80%, about 75%, about 70%, about 65%, about 60%, or about 55%;about 55% to about 99%, about 95%, about 90%, about 85%, about 80%,about 75%, about 70%, about 65%, or about 60%; about 60% to about 99%,about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, orabout 65%; about 65% to about 99%, about 95%, about 90%, about 85%,about 80%, about 75%, or about 70%; about 70% to about 99%, about 95%,about 90%, about 85%, about 80%, or about 75%; about 75% to about 99%,about 95%, about 90%, about 85%, or about 80%; about 80% to about 99%,about 95%, about 90%, or about 85%; about 85% to about 99%, about 95%,or about 90%; about 90% to about 99% or about 90%; or about 95% to about99% as compared to the risk of developing a metastasis or an additionalmetastasis in the patient prior to treatment, or as compared to apatient or a population of patients having a similar or the sameFGFR-associated cancer that has received no treatment or a differenttreatment.

In some examples, the risk of developing a metastasis or an additionalmetastasis is over about 2 weeks, 1 month, 1.5 months, 2 months, 2.5months, 3 months, 3.5 months, 4 months, 4.5 months, 5 months, 5.5months, 6 months, 6.5 months, 7 months, 7.5 months, 8 months, 8.5months, 9 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5months, 12 months, 1.5 years, 2 years, 2.5 years, 3 years, 3.5 years, 4years, 4.5 years, 5 years, 5.5 years, 6 years, 6.5 years, 7 years, 7.5years, 8 years, 8.5 years, 9 years, 9.5 years, or 10 years.

Also provided is the use of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof for decreasing therisk of developing a metastasis or an additional metastasis in a patienthaving a FGFR-associated cancer. Also provided is the use of a compoundof Formula I or a pharmaceutically acceptable salt or solvate thereoffor the manufacture of a medicament for decreasing the risk ofdeveloping a metastasis or an additional metastasis in a patient havinga FGFR-associated cancer.

In some embodiments, the FGFR-associated cancer is a FGFR-associatedcancer having one or more FGFR inhibitor resistance mutations. In someembodiments, the additional therapeutic agent is crizotinib. In someembodiments, the additional therapeutic agent is osimertinib. In someembodiments, the subject has been administered one or more doses of acompound of Formula I, or a pharmaceutically acceptable salt thereof,prior to administration of the pharmaceutical composition. In someembodiments, the cancer is a bladder cancer (e.g., a FGFR-associatedbladder cancer).

The phrase “risk of developing a metastasis” means the risk that asubject or patient having a primary tumor will develop an additionaltumor (e.g., a solid tumor) at a site distant from a primary tumor in asubject or patient over a set period of time, where the additional tumorincludes the same or similar cancer cells as the primary tumor. Methodsfor reducing the risk of developing a metastasis in a subject or patienthaving a cancer are described herein.

The phrase “risk of developing additional metastases” means the riskthat a subject or patient having a primary tumor and one or moreadditional tumors at sites distant from the primary tumor (where the oneor more additional tumors include the same or similar cancer cells asthe primary tumor) will develop one or more further tumors distant fromthe primary tumor, where the further tumors include the same or similarcancer cells as the primary tumor. Methods for reducing the risk ofdeveloping additional metastasis are described herein.

In some embodiments, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting a dysregulation of a FGFR gene, a FGFRkinase, or the expression or activity or level of any of the same in asample from the subject; and (b) administering to the subject atherapeutically effective amount of a multikinase inhibitor (MKI) or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a cancer cell in a sample obtained from the subject has at leastone FGFR inhibitor resistance mutation; and (d) administering a compoundof Formula I, or a pharmaceutically acceptable salt or solvate thereofas a monotherapy or in conjunction with an additional therapy ortherapeutic agent to the subject if the subject has a cancer cell thathas at least one FGFR inhibitor resistance mutation; or (e)administering additional doses of the multikinase inhibitor of step (b)to the subject if the subject has a cancer cell that does not have aFGFR inhibitor resistance mutation. In some embodiments of any of themethods disclosed herein, a multikinase inhibitor can be selected fromthe group consisting of brivanib, dovitinib, erdafitinib, lenvatinib,lucitanib, nintedanib, orantinib, pemigatinib, ponatinib, rogaratinib,and sulfatinib.

In some embodiments, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting a dysregulation of a FGFR gene, a FGFRkinase, or the expression or activity or level of any of the same in asample from the subject; and (b) administering to the subject atherapeutically effective amount of a first multikinase inhibitor or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a cancer cell in a sample obtained from the subject has at leastone FGFR inhibitor resistance mutation; and (d) administering a compoundof Formula I selected from Examples 1-30, or a pharmaceuticallyacceptable salt or solvate thereof as a monotherapy or in conjunctionwith an additional therapy or therapeutic agent to the subject if thesubject has a cancer cell that has at least one FGFR inhibitorresistance mutation; or (e) administering additional doses of themultikinase inhibitor of step (b) to the subject if the subject has acancer cell that does not have a FGFR inhibitor resistance mutation. Insome embodiments of any of the methods disclosed herein, a multikinaseinhibitor can be selected from the group consisting of brivanib,dovitinib, erdafitinib, lenvatinib, lucitanib, nintedanib, orantinib,pemigatinib, ponatinib, rogaratinib, and sulfatinib.

In some embodiments, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting one or more fusion proteins of Table BAand/or one or more FGFR kinase protein pointmutations/insertions/deletions of Table BC a sample from the subject;and (b) administering to the subject a therapeutically effective amountof a multikinase inhibitor or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments, the methods further comprise(after (b)) (c) determining whether a cancer cell in a sample obtainedfrom the subject has at least one FGFR inhibitor resistance mutation ofTable BE; and (d) administering a compound of Formula I or apharmaceutically acceptable salt or solvate thereof as a monotherapy orin conjunction with an additional therapy or therapeutic agent to thesubject if the subject has a cancer cell that has at least one FGFRinhibitor resistance mutation; or (e) administering additional doses ofthe multikinase inhibitor of step (b) to the subject if the subject hasa cancer cell that does not have a FGFR inhibitor resistance mutation.In some embodiments of any of the methods disclosed herein, amultikinase inhibitor can be selected from the group consisting ofbrivanib, dovitinib, erdafitinib, lenvatinib, lucitanib, nintedanib,orantinib, pemigatinib, ponatinib, rogaratinib, and sulfatinib.

In some embodiments, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting one or more fusion proteins of Table BAand/or one or more FGFR kinase protein pointmutations/insertions/deletions of Table BC a sample from the subject;and (b) administering to the subject a therapeutically effective amountof a multikinase inhibitor or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments, the methods further comprise(after (b)) (c) determining whether a cancer cell in a sample obtainedfrom the subject has at least one FGFR inhibitor resistance mutation ofTable BE; and (d) administering a compound of Formula I selected fromExamples 1-30, or a pharmaceutically acceptable salt or solvate thereofas a monotherapy or in conjunction with an additional therapy ortherapeutic agent to the subject if the subject has a cancer cell thathas at least one FGFR inhibitor resistance mutation; or (e)administering additional doses of the multikinase inhibitor of step (b)to the subject if the subject has a cancer cell that does not have aFGFR inhibitor resistance mutation. In some embodiments of any of themethods disclosed herein, a multikinase inhibitor can be selected fromthe group consisting of brivanib, dovitinib, erdafitinib, lenvatinib,lucitanib, nintedanib, orantinib, pemigatinib, ponatinib, rogaratinib,and sulfatinib.

In some embodiments, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting the fusion protein FGFR3-TACC3 in asample from the subject; and (b) administering to the subject atherapeutically effective amount of a multikinase inhibitor or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a cancer cell in a sample obtained from the subject has a FGFRinhibitor resistance mutation corresponding to V561M in SEQ ID NO. 1,V564I or V564F in SEQ ID NO. 3, or V555M in SEQ ID NO. 5; and (d)administering a compound of Formula I or a pharmaceutically acceptablesalt or solvate thereof selected from the group consisting of a compoundof Formula I or a pharmaceutically acceptable salt or solvate thereof asa monotherapy or in conjunction with an additional therapy ortherapeutic agent to the subject if the subject has a cancer cell thathas at least one FGFR inhibitor resistance mutation; or (e)administering additional doses of the multikinase inhibitor of step (b)to the subject if the subject has a cancer cell that does not have aFGFR inhibitor resistance mutation. In some embodiments of any of themethods disclosed herein, a multikinase inhibitor can be selected fromthe group consisting of brivanib, dovitinib, erdafitinib, lenvatinib,lucitanib, nintedanib, orantinib, pemigatinib, ponatinib, rogaratinib,and sulfatinib.

In some embodiments, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting the fusion protein FGFR3-TACC3 in asample from the subject; and (b) administering to the subject atherapeutically effective amount of a multikinase inhibitor or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a cancer cell in a sample obtained from the subject has the FGFRinhibitor resistance mutation corresponding to V561M in SEQ ID NO. 1,V564I or V564F in SEQ ID NO. 3, or V555M in SEQ ID NO. 5; and (d)administering a compound of Formula I or a pharmaceutically acceptablesalt or solvate thereof selected from the group consisting of a compoundof Formula I selected from Examples 1-30, or a pharmaceuticallyacceptable salt or solvate thereof as a monotherapy or in conjunctionwith an additional therapy or therapeutic agent to the subject if thesubject has a cancer cell that has at least one FGFR inhibitorresistance mutation; or (e) administering additional doses of themultikinase inhibitor of step (b) to the subject if the subject has acancer cell that does not have a FGFR inhibitor resistance mutation. Insome embodiments of any of the methods disclosed herein, a multikinaseinhibitor can be selected from the group consisting of brivanib,dovitinib, erdafitinib, lenvatinib, lucitanib, nintedanib, orantinib,pemigatinib, ponatinib, rogaratinib, and sulfatinib.

In some embodiments, the presence of one or more FGFR inhibitorresistance mutations in a tumor causes the tumor to be more resistant totreatment with a first FGFR inhibitor. Methods useful when a FGFRinhibitor resistance mutation causes the tumor to be more resistant totreatment with a first FGFR inhibitor are described below. For example,provided herein are methods of treating a subject having a cancer thatinclude: identifying a subject having a cancer cell that has one or moreFGFR inhibitor resistance mutations; and administering to the identifiedsubject a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments, the compound of Formula I or apharmaceutically acceptable salt or solvate thereof is administered incombination with the first FGFR inhibitor. Also provided are methods oftreating a subject identified as having a cancer cell that has one ormore FGFR inhibitor resistance mutations that include administering tothe subject a compound of Formula I or a pharmaceutically acceptablesalt or solvate thereof. In some embodiments, the compound of Formula Ior a pharmaceutically acceptable salt or solvate thereof is administeredin combination with the first FGFR inhibitor. In some embodiments, theone or more FGFR inhibitor resistance mutations confer increasedresistance to a cancer cell or tumor to treatment with the first FGFRinhibitor. In some embodiments, the one or more FGFR inhibitorresistance mutations include one or more FGFR inhibitor resistancemutations listed in Table BE. For example, the one or more FGFRinhibitor resistance mutations can include a substitution at an aminoacid position corresponding to amino acid position 561 in SEQ ID NO. 1(e.g., V561M), amino acid position 564 in SEQ ID NO. 3 (e.g., V564I orV564F), or amino acid position 555 in SEQ ID NO. 5 (e.g., V555M).

For example, provided herein are methods for treating a FGFR-associatedcancer in a subject in need of such treatment, the method comprising (a)detecting a dysregulation of a FGFR gene, a FGFR kinase, or theexpression or activity or level of any of the same in a sample from thesubject; and (b) administering to the subject a therapeuticallyeffective amount of a first FGFR inhibitor, wherein the first FGFRinhibitor is selected from the group consisting of ARQ-087, ASP5878,AZD4547, B-701, BAY1179470, BAY1187982, BGJ398, brivanib, Debio 1347,dovitinib, E7090, erdafitinib, FPA144, HMPL-453, INCB054828, lenvatinib,lucitanib, LY3076226, MAX-40279, nintedanib, orantinib, pemigatinib,ponatinib, PRN1371, rogaratinib, sulfatinib, and TAS-120. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a cancer cell in a sample obtained from the subject has at leastone FGFR inhibitor resistance mutation; and (d) administering a compoundof Formula I, or a pharmaceutically acceptable salt or solvate thereofas a monotherapy or in conjunction with an additional therapy ortherapeutic agent to the subject if the subject has a cancer cell thathas at least one FGFR inhibitor resistance mutation; or (e)administering additional doses of the first FGFR inhibitor of step (b)to the subject if the subject has a cancer cell that does not have aFGFR inhibitor resistance mutation.

In some embodiments, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting a dysregulation of a FGFR gene, a FGFRkinase, or the expression or activity or level of any of the same in asample from the subject; and (b) administering to the subject atherapeutically effective amount of a first FGFR inhibitor, wherein thefirst FGFR inhibitor is selected from the group consisting of ARQ-087,ASP5878, AZD4547, B-701, BAY1179470, BAY1187982, BGJ398, brivanib, Debio1347, dovitinib, E7090, erdafitinib, FPA144, HMPL-453, INCB054828,lenvatinib, lucitanib, LY3076226, MAX-40279, nintedanib, orantinib,pemigatinib, ponatinib, PRN1371, rogaratinib, sulfatinib, and TAS-120.In some embodiments, the methods further comprise (after (b)) (c)determining whether a cancer cell in a sample obtained from the subjecthas at least one FGFR inhibitor resistance mutation; and (d)administering a compound of Formula I selected from Examples 1-30, or apharmaceutically acceptable salt or solvate thereof as a monotherapy orin conjunction with an additional therapy or therapeutic agent to thesubject if the subject has a cancer cell that has at least one FGFRinhibitor resistance mutation; or (e) administering additional doses ofthe first FGFR inhibitor of step (b) to the subject if the subject has acancer cell that does not have a FGFR inhibitor resistance mutation.

In some embodiments, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting one or more fusion proteins of Table BAand/or one or more FGFR kinase protein pointmutations/insertions/deletions of Table BC in a sample from the subject;and (b) administering to the subject a therapeutically effective amountof a first FGFR inhibitor, wherein the first FGFR inhibitor is selectedfrom the group consisting of ARQ-087, ASP5878, AZD4547, B-701,BAY1179470, BAY1187982, BGJ398, brivanib, Debio 1347, dovitinib, E7090,erdafitinib, FPA144, HMPL-453, INCB054828, lenvatinib, lucitanib,LY3076226, MAX-40279, nintedanib, orantinib, pemigatinib, ponatinib,PRN1371, rogaratinib, sulfatinib, and TAS-120. In some embodiments, themethods further comprise (after (b)) (c) determining whether a cancercell in a sample obtained from the subject has at least one FGFRinhibitor resistance mutation of Table BE; and (d) administering acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof as a monotherapy or in conjunction with an additional therapy ortherapeutic agent to the subject if the subject has a cancer cell thathas at least one FGFR inhibitor resistance mutation; or (e)administering additional doses of the first FGFR inhibitor of step (b)to the subject if the subject has a cancer cell that does not have aFGFR inhibitor resistance mutation.

In some embodiments, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting one or more fusion proteins of Table BAand/or one or more FGFR kinase protein pointmutations/insertions/deletions of Table BC in a sample from the subject;and (b) administering to the subject a therapeutically effective amountof a first FGFR inhibitor, wherein the first FGFR inhibitor is selectedfrom the group consisting of ARQ-087, ASP5878, AZD4547, B-701,BAY1179470, BAY1187982, BGJ398, brivanib, Debio 1347, dovitinib, E7090,erdafitinib, FPA144, HMPL-453, INCB054828, lenvatinib, lucitanib,LY3076226, MAX-40279, nintedanib, orantinib, pemigatinib, ponatinib,PRN1371, rogaratinib, sulfatinib, and TAS-120. In some embodiments, themethods further comprise (after (b)) (c) determining whether a cancercell in a sample obtained from the subject has at least one FGFRinhibitor resistance mutation of Table BE; and (d) administering acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof as a monotherapy or in conjunction with an additional therapy ortherapeutic agent to the subject if the subject has a cancer cell thathas at least one FGFR inhibitor resistance mutation; or (e)administering additional doses of the first FGFR inhibitor of step (b)to the subject if the subject has a cancer cell that does not have aFGFR inhibitor resistance mutation.

In some embodiments, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting one or more fusion proteins of Table BAand/or one or more FGFR kinase protein pointmutations/insertions/deletions of Table BC in a sample from the subject;and (b) administering to the subject a therapeutically effective amountof a first FGFR inhibitor, wherein the first FGFR inhibitor is selectedfrom the group consisting of ARQ-087, ASP5878, AZD4547, B-701,BAY1179470, BAY1187982, BGJ398, brivanib, Debio 1347, dovitinib, E7090,erdafitinib, FPA144, HMPL-453, INCB054828, lenvatinib, lucitanib,LY3076226, MAX-40279, nintedanib, orantinib, pemigatinib, ponatinib,PRN1371, rogaratinib, sulfatinib, and TAS-120. In some embodiments, themethods further comprise (after (b)) (c) determining whether a cancercell in a sample obtained from the subject has at least one FGFRinhibitor resistance mutation of Table BE; and (d) administering acompound of Formula I selected from Examples 1-30, or a pharmaceuticallyacceptable salt or solvate thereof as a monotherapy or in conjunctionwith an additional therapy or therapeutic agent to the subject if thesubject has a cancer cell that has at least one FGFR inhibitorresistance mutation; or (e) administering additional doses of the firstFGFR inhibitor of step (b) to the subject if the subject has a cancercell that does not have a FGFR inhibitor resistance mutation.

In some embodiments, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting the fusion protein FGFR3-TACC3 in asample from the subject; and (b) administering to the subject atherapeutically effective amount of a first FGFR inhibitor, wherein thefirst FGFR inhibitor is selected from the group consisting of ARQ-087,ASP5878, AZD4547, B-701, BAY1179470, BAY1187982, BGJ398, brivanib, Debio1347, dovitinib, E7090, erdafitinib, FPA144, HMPL-453, INCB054828,lenvatinib, lucitanib, LY3076226, MAX-40279, nintedanib, orantinib,pemigatinib, ponatinib, PRN1371, rogaratinib, sulfatinib, and TAS-120.In some embodiments, the methods further comprise (after (b)) (c)determining whether a cancer cell in a sample obtained from the subjecthas the FGFR inhibitor resistance mutation corresponding to V561M in SEQID NO. 1, V564I or V564F in SEQ ID NO. 3, or V555M in SEQ ID NO. 5; and(d) administering a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof selected from the group consisting ofa compound of Formula I or a pharmaceutically acceptable salt or solvatethereof as a monotherapy or in conjunction with an additional therapy ortherapeutic agent to the subject if the subject has a cancer cell thathas at least one FGFR inhibitor resistance mutation; or (e)administering additional doses of the first FGFR inhibitor of step (b)to the subject if the subject has a cancer cell that does not have aFGFR inhibitor resistance mutation.

In some embodiments, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting the fusion protein FGFR3-TACC3 in asample from the subject; and (b) administering to the subject atherapeutically effective amount of a first FGFR inhibitor, wherein thefirst FGFR inhibitor is selected from the group consisting of ARQ-087,ASP5878, AZD4547, B-701, BAY1179470, BAY1187982, BGJ398, brivanib, Debio1347, dovitinib, E7090, erdafitinib, FPA144, HMPL-453, INCB054828,lenvatinib, lucitanib, LY3076226, MAX-40279, nintedanib, orantinib,pemigatinib, ponatinib, PRN1371, rogaratinib, sulfatinib, and TAS-120.In some embodiments, the methods further comprise (after (b)) (c)determining whether a cancer cell in a sample obtained from the subjecthas the FGFR inhibitor resistance mutation corresponding to V561M in SEQID NO. 1, V564I or V564F in SEQ ID NO. 3, or V555M in SEQ ID NO. 5; and(d) administering a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof selected from the group consisting ofa compound of Formula I selected from Examples 1-30, or apharmaceutically acceptable salt or solvate thereof as a monotherapy orin conjunction with an additional therapy or therapeutic agent to thesubject if the subject has a cancer cell that has at least one FGFRinhibitor resistance mutation; or (e) administering additional doses ofthe first FGFR inhibitor of step (b) to the subject if the subject has acancer cell that does not have a FGFR inhibitor resistance mutation.

Also provided are methods of treating a subject having a cancer thatinclude: (a) administering one or more doses of a first FGFR inhibitorto the subject for a period of time; (b) after (a), determining whethera cancer cell in a sample obtained from the subject has at least oneFGFR inhibitor resistance mutation; and (c) administering a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof as amonotherapy or in conjunction with an additional therapy or therapeuticagent to the subject if the subject has a cancer cell that has at leastone FGFR inhibitor resistance mutation; or (d) administering additionaldoses of the first FGFR inhibitor of step (a) to the subject if thesubject has a cancer cell that does not have a FGFR inhibitor resistancemutation. In some embodiments, where the subject is administeredadditional doses of the first FGFR inhibitor of step (a), the subjectcan also be administered an additional therapy or therapeutic agent(e.g., a second FGFR inhibitor or a compound of Formula I or apharmaceutically acceptable salt or solvate thereof, or immunotherapy).In some embodiments, the additional therapy or therapeutic agent is anyanticancer agent known in the art. For example, the additional therapyor therapeutic agent is another FGFR inhibitor (e.g., a second FGFRinhibitor). In some embodiments, the additional therapy or therapeuticagent is an immunotherapy. In some embodiments of step (c), another FGFRinhibitor can be the first FGFR inhibitor administered in step (a). Insome embodiments, the one or more FGFR inhibitor resistance mutationsconfer increased resistance to a cancer cell or tumor to treatment withthe first FGFR inhibitor. In some embodiments, the one or more FGFRinhibitor resistance mutations include one or more FGFR inhibitorresistance mutations listed in Table BE. For example, the one or moreFGFR inhibitor resistance mutations can include a substitution at anamino acid position corresponding to amino acid position 561 in SEQ IDNO. 1 (e.g., V561M), amino acid position 564 in SEQ ID NO. 3 (e.g.,V564I or V564F), or amino acid position 555 in SEQ ID NO. 5 (e.g.,V555M).

Also provided are methods of treating a subject having a cancer thatinclude: (a) administering one or more doses of a first FGFR inhibitorto the subject for a period of time; (b) after (a), determining whethera cancer cell in a sample obtained from the subject has at least oneFGFR inhibitor resistance mutation; and (c) administering a second FGFRinhibitor as a monotherapy or in conjunction with an additional therapyor therapeutic agent to the subject if the subject has a cancer cellthat has at least one FGFR inhibitor resistance mutation; or (d)administering additional doses of the first FGFR inhibitor step (a) tothe subject if the subject has a cancer cell that does not have a FGFRinhibitor resistance mutation. In some embodiments, where the subject isadministered additional doses of the first FGFR inhibitor of step (a),the subject can also be administered an additional therapy ortherapeutic agent. In some embodiments, the one or more FGFR inhibitorresistance mutations confer increased resistance to a cancer cell ortumor to treatment with the first FGFR inhibitor. In some embodiments,the one or more FGFR inhibitor resistance mutations include one or moreFGFR inhibitor resistance mutations listed Table BE. For example, theone or more FGFR inhibitor resistance mutations can include asubstitution at an amino acid position corresponding to amino acidposition 561 in SEQ ID NO. 1 (e.g., V561M), amino acid position 564 inSEQ ID NO. 3 (e.g., V564I or V564F), or amino acid position 555 in SEQID NO. 5 (e.g., V555M). In some embodiments, the additional therapy ortherapeutic agent is any anticancer agent known in the art. For example,the additional therapy or therapeutic agent is another FGFR inhibitor(e.g., a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof). In some embodiments, the additional therapy ortherapeutic agent is an immunotherapy. In some embodiments, a compoundof Formula I is at least about 3-fold more selective for FGFR3 overFGFR1. In some embodiments, a compound of Formula I is at least about3-fold more selective for FGFR2 over FGFR1.

Also provided are methods of treating a subject having a cancer (e.g., aFGFR-associated cancer) that include: (a) determining whether a cancercell in a sample obtained from a subject having a cancer and previouslyadministered one or more doses of a first FGFR inhibitor, has one ormore FGFR inhibitor resistance mutations; and (b) administering acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof as a monotherapy or in conjunction with an additional therapy ortherapeutic agent to the subject if the subject has a cancer cell thathas at least one FGFR inhibitor resistance mutation; or (c)administering additional doses of the first FGFR inhibitor previouslyadministered to the subject if the subject has cancer cell that does nothave a FGFR inhibitor resistance mutation. In some embodiments, wherethe subject is administered additional doses of the first FGFR inhibitorpreviously administered to the subject, the subject can also beadministered an additional therapy or therapeutic agent (e.g., acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof, or immunotherapy). In some embodiments, the one or more FGFRinhibitor resistance mutations confer increased resistance to a cancercell or tumor to treatment with the first FGFR inhibitor. In someembodiments, the one or more FGFR inhibitor resistance mutations includeone or more FGFR inhibitor resistance mutations listed in Table BE. Forexample, the one or more FGFR inhibitor resistance mutations can includea substitution at an amino acid position corresponding to amino acidposition 561 in SEQ ID NO. 1 (e.g., V561M), amino acid position 564 inSEQ ID NO. 3 (e.g., V564I or V564F), or amino acid position 555 in SEQID NO. 5 (e.g., V555M). In some embodiments, the additional therapy ortherapeutic agent is any anticancer agent known in the art. For example,the additional therapy or therapeutic agent is another FGFR inhibitor(e.g., a second FGFR inhibitor). In some embodiments, the additionaltherapy or therapeutic agent is an immunotherapy. In some embodiments ofstep (b), the additional therapy or therapeutic agent can be the firstFGFR inhibitor administered in step (a).

Also provided are methods of treating a subject having a cancer thatinclude: (a) determining whether a cancer cell in a sample obtained froma subject having a cancer and previously administered one or more dosesof a first FGFR inhibitor has one or more FGFR inhibitor resistancemutations; and (b) administering a second FGFR inhibitor as amonotherapy or in conjunction with an additional therapy or therapeuticagent to the subject if the subject has a cancer cell that has at leastone FGFR inhibitor resistance mutation; or (c) administering additionaldoses of the first FGFR inhibitor previously administered to the subjectif the subject has a cancer cell that does not have a FGFR inhibitorresistance mutation. In some embodiments, where the subject isadministered additional doses of the first FGFR inhibitor previouslyadministered to the subject, the subject can also be administered anadditional therapy or therapeutic agent. In some embodiments, the one ormore FGFR inhibitor resistance mutations confer increased resistance toa cancer cell or tumor to treatment with the first FGFR inhibitor. Insome embodiments, the one or more FGFR inhibitor resistance mutationsinclude one or more FGFR inhibitor resistance mutations listed in TableBE. For example, the one or more FGFR inhibitor resistance mutations caninclude a substitution at an amino acid position corresponding to aminoacid position 561 in SEQ ID NO. 1 (e.g., V561M), amino acid position 564in SEQ ID NO. 3 (e.g., V564I or V564F), or amino acid position 555 inSEQ ID NO. 5 (e.g., V555M). In some embodiments, the additional therapyor therapeutic agent is any anticancer agent known in the art. Forexample, the additional therapy or therapeutic agent is another FGFRinhibitor (e.g., a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof). In some embodiments, the additionaltherapy or therapeutic agent is an immunotherapy. In some embodiments of(b), the additional therapy or therapeutic agent can be the first FGFRinhibitor administered in step (a).

In some embodiments of any of the methods described herein, a FGFRinhibitor resistance mutation that confers increased resistance to acancer cell or tumor to treatment with a first FGFR inhibitor can be anyof the FGFR inhibitor resistance mutations listed in Table BE (e.g., asubstitution at an amino acid position corresponding to amino acidposition 561 in SEQ ID NO. 1 (e.g., V561M), amino acid position 564 inSEQ ID NO. 3 (e.g., V564I or V564F), or amino acid position 555 in SEQID NO. 5 (e.g., V555M)).

Methods of determining the level of resistance of a cancer cell or atumor to a FGFR inhibitor (e.g., any of the FGFR inhibitors describedherein or known in the art) can be determined using methods known in theart. For example, the level of resistance of a cancer cell to a FGFRinhibitor can be assessed by determining the IC₅₀ of a FGFR inhibitor(e.g., any of the FGFR inhibitors described herein or known in the art)on the viability of a cancer cell. In other examples, the level ofresistance of a cancer cell to a FGFR inhibitor can be assessed bydetermining the growth rate of the cancer cell in the presence of a FGFRinhibitor (e.g., any of the FGFR inhibitors described herein). In otherexamples, the level of resistance of a tumor to a FGFR inhibitor can beassessed by determining the mass or size of one or more tumors in asubject over time during treatment with a FGFR inhibitor (e.g., any ofthe FGFR inhibitors described herein). In other examples, the level ofresistance of a cancer cell or a tumor to a FGFR inhibitor can beindirectly assessed by determining the activity of a FGFR kinaseincluding one or more of the FGFR inhibitor resistance mutations (i.e.,the same FGFR kinase expressed in a cancer cell or a tumor in asubject). The level of resistance of a cancer cell or tumor having oneor more FGFR inhibitor resistance mutations to a FGFR inhibitor isrelative to the level of resistance in a cancer cell or tumor that doesnot have a FGFR inhibitor resistance mutation (e.g., a cancer cell ortumor that does not have the same FGFR inhibitor resistance mutations, acancer cell or a tumor that does not have any FGFR inhibitor resistancemutations, or a cancer cell or a tumor that expresses a wildtype FGFRprotein). For example, the determined level of resistance of a cancercell or a tumor having one or more FGFR inhibitor resistance mutationscan be greater than about 1%, greater than about 2%, greater than about3%, greater than about 4%, greater than about 5%, greater than about 6%,greater than about 7%, greater than about 8%, greater than about 9%,greater than about 10%, greater than about 11%, greater than about 12%,greater than about 13%, greater than about 14%, greater than about 15%,greater than about 20%, greater than about 25%, greater than about 30%,greater than about 35%, greater than about 40%, greater than about 45%,greater than about 50%, greater than about 60%, greater than about 70%,greater than about 80%, greater than about 90%, greater than about 100%,greater than about 110%, greater than about 120%, greater than about130%, greater than about 140%, greater than about 150%, greater thanabout 160%, greater than about 170%, greater than about 180%, greaterthan about 190%, greater than about 200%, greater than about 210%,greater than about 220%, greater than about 230%, greater than about240%, greater than about 250%, greater than about 260%, greater thanabout 270%, greater than about 280%, greater than about 290%, or greaterthan about 300% of the level of resistance in a cancer cell or tumorthat does not have a FGFR inhibitor resistance mutation (e.g., a cancercell or tumor that does not have the same FGFR inhibitor resistancemutations, a cancer cell or a tumor that does not have any FGFRinhibitor resistance mutations, or a cancer cell or a tumor thatexpresses a wildtype FGFR protein).

In some embodiments, the presence of one or more FGFR inhibitorresistance mutations in a tumor causes the tumor to be more resistant totreatment with a compound of Formula I or a pharmaceutically acceptablesalt or solvate thereof. Methods useful when a FGFR inhibitor resistancemutation causes the tumor to be more resistant to treatment with acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof are described below. For example, provided herein are methods oftreating a subject having a cancer that include: identifying a subjecthaving a cancer cell that has one or more FGFR inhibitor resistancemutations; and administering to the identified subject a treatment thatdoes not include a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof as a monotherapy or in conjunctionwith an additional therapy or therapeutic agent (e.g., a second FGFRkinase inhibitor). Also provided are methods of treating a subjectidentified as having a cancer cell that has one or more FGFR inhibitorresistance mutations that include administering to the subject atreatment that does not include a compound of Formula I or apharmaceutically acceptable salt or solvate thereof as a monotherapy orin conjunction with an additional therapy or therapeutic agent (e.g., asecond FGFR kinase inhibitor). In some embodiments, the one or more FGFRinhibitor resistance mutations confer increased resistance to a cancercell or tumor to treatment with a compound of Formula I or apharmaceutically acceptable salt or solvate thereof.

Also provided are methods of treating a subject having a cancer thatinclude: (a) administering one or more doses of a compound of Formula Ior a pharmaceutically acceptable salt or solvate thereof for a period oftime; (b) after (a), determining whether a cancer cell in a sampleobtained from the subject has one or more FGFR inhibitor resistancemutations; and (c) administering a second FGFR inhibitor or a secondcompound of Formula I or a pharmaceutically acceptable salt or solvatethereof as a monotherapy or in conjunction with an additional therapy ortherapeutic agent to a subject having a cancer cell that has one or moreFGFR inhibitor resistance mutations; or (d) administering additionaldoses of the compound of Formula I or a pharmaceutically acceptable saltor solvate thereof of step (a) to a subject having a cancer cell thatdoes not have a FGFR inhibitor resistance mutation. In some embodiments,where the subject is administered additional doses of the compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof ofstep (a), the subject can also be administered an additional therapy ortherapeutic agent or a second compound of Formula I or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the one or more FGFR inhibitor resistance mutations conferincreased resistance to a cancer cell or tumor to treatment with acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof. In some embodiments, the additional therapy or therapeuticagent is any anticancer agent known in the art. For example, theadditional therapy or therapeutic agent is another FGFR inhibitor (e.g.,a second FGFR inhibitor). In some embodiments, the additional therapy ortherapeutic agent is an immunotherapy. In some embodiments, another FGFRinhibitor can be the compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof administered in step (a).

Also provided are methods of treating a subject having a cancer thatinclude: (a) determining whether a cancer cell in a sample obtained froma subject having a cancer and previously administered one or more dosesof a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof, has one or more FGFR inhibitor resistance mutations;(b) administering a second FGFR inhibitor or a second compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof as amonotherapy or in conjunction with an additional therapy or therapeuticagent to a subject having a cancer cell that has one or more FGFRinhibitor resistance mutations; or (c) administering additional doses ofthe compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof previously administered to a subject having a cancercell that does not have a FGFR inhibitor resistance mutation. In someembodiments, where the subject is administered additional doses of thecompound of Formula I or a pharmaceutically acceptable salt or solvatethereof of step (a), the subject can also be administered an additionaltherapy or therapeutic agent. In some embodiments, the one or more FGFRinhibitor resistance mutations confer increased resistance to a cancercell or tumor to treatment with a compound of Formula I or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the additional therapy or therapeutic agent is anyanticancer agent known in the art. For example, the additional therapyor therapeutic agent is another FGFR inhibitor (e.g., a second FGFRinhibitor). In some embodiments, the additional therapy or therapeuticagent is an immunotherapy. In some embodiments, another FGFR inhibitorcan be the compound of Formula I or a pharmaceutically acceptable saltor solvate thereof administered in step (a).

In some embodiments of any of the methods described herein, a FGFRinhibitor resistance mutation that confers increased resistance to acancer cell or tumor to treatment with a compound of Formula I or apharmaceutically acceptable salt or solvate thereof, can be any of theFGFR inhibitor resistance mutations listed in Table BE.

Also, provided herein are methods for treating a FGFR-associated cancerin a subject in need of such treatment, the method comprising (a)detecting a dysregulation of a FGFR gene, a FGFR kinase, or theexpression or activity or level of any of the same in a sample from thesubject; and (b) administering to the subject a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof. In some embodiments, the methodsfurther comprise (after (b)) (c) determining whether a cancer cell in asample obtained from the subject has at least one FGFR inhibitorresistance mutation; and (d) administering additional doses of thecompound of Formula I or a pharmaceutically acceptable salt or solvatethereof of step (b) to the subject as a monotherapy or in conjunctionwith an additional therapy or therapeutic agent (e.g., a second FGFRinhibitor, a second compound of Formula I or a pharmaceuticallyacceptable salt thereof, or immunotherapy) or anticancer therapy (e.g.,surgery or radiation) if the subject has a cancer cell that has at leastone FGFR inhibitor resistance mutation. Also, provided herein aremethods for treating a FGFR-associated cancer in a subject in need ofsuch treatment, the method comprising (a) detecting a dysregulation of aFGFR gene, a FGFR kinase, or the expression or activity or level of anyof the same in a sample from the subject; and (b) administering to thesubject a therapeutically effective amount of a compound of Formula Iselected from the group consisting of Examples 1-30 or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a cancer cell in a sample obtained from the subject has at leastone FGFR inhibitor resistance mutation; and (d) administering additionaldoses of the compound of Formula I or a pharmaceutically acceptable saltor solvate thereof of step (b) to the subject as a monotherapy or inconjunction with an additional therapy or therapeutic agent (e.g., asecond FGFR inhibitor, a second compound of Formula I or apharmaceutically acceptable salt thereof, or immunotherapy) oranticancer therapy (e.g., surgery or radiation) if the subject has acancer cell that has at least one FGFR inhibitor resistance mutation. Insome embodiments, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting one or more fusion proteins of Table BAand/or one or more FGFR kinase protein pointmutations/insertions/deletions of Table BC in a sample from the subject;and (b) administering to the subject a therapeutically effective amountof a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof selected from the group consisting of a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the methods further comprise (after (b)) (c)determining whether a cancer cell in a sample obtained from the subjecthas at least one FGFR inhibitor resistance mutation of Table BE; and (d)administering additional doses of the compound of Formula I or apharmaceutically acceptable salt or solvate thereof of step (b) to thesubject as a monotherapy or in conjunction with an additional therapy ortherapeutic agent (e.g., a second FGFR inhibitor, a second compound ofFormula I or a pharmaceutically acceptable salt thereof, orimmunotherapy) or anticancer therapy (e.g., surgery or radiation) if thesubject has a cancer cell that has at least one FGFR inhibitorresistance mutation. In some embodiments, a second FGFR inhibitorselected from the group consisting of ARQ-087, ASP5878, AZD4547, B-701,BAY1179470, BAY1187982, BGJ398, brivanib, Debio 1347, dovitinib, E7090,erdafitinib, FPA144, HMPL-453, INCB054828, lenvatinib, lucitanib,LY3076226, MAX-40279, nintedanib, orantinib, pemigatinib, ponatinib,PRN1371, rogaratinib, sulfatinib, and TAS-120 is administered in step(d). In some embodiments, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting one or more fusion proteins of Table BAand/or one or more FGFR kinase protein pointmutations/insertions/deletions of Table BC in a sample from the subject;and (b) administering to the subject a therapeutically effective amountof a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof selected from the group consisting of a compound ofFormula I selected from Examples 1-30, or a pharmaceutically acceptablesalt or solvate thereof. In some embodiments, the methods furthercomprise (after (b)) (c) determining whether a cancer cell in a sampleobtained from the subject has at least one FGFR inhibitor resistancemutation of Table BE; and (d) administering additional doses of thecompound of Formula I or a pharmaceutically acceptable salt or solvatethereof of step (b) to the subject as a monotherapy or in conjunctionwith an additional therapy or therapeutic agent (e.g., a second FGFRinhibitor, a second compound of Formula I or a pharmaceuticallyacceptable salt thereof, or immunotherapy) or anticancer therapy (e.g.,surgery or radiation) if the subject has a cancer cell that has at leastone FGFR inhibitor resistance mutation. In some embodiments, a secondFGFR inhibitor selected from the group consisting of ARQ-087, ASP5878,AZD4547, B-701, BAY1179470, BAY1187982, BGJ398, brivanib, Debio 1347,dovitinib, E7090, erdafitinib, FPA144, HMPL-453, INCB054828, lenvatinib,lucitanib, LY3076226, MAX-40279, nintedanib, orantinib, pemigatinib,ponatinib, PRN1371, rogaratinib, sulfatinib, and TAS-120 is administeredin step (d). In some embodiments, provided herein are methods fortreating a FGFR-associated cancer in a subject in need of suchtreatment, the method comprising (a) detecting the fusion proteinFGFR3-TACC3 in a sample from the subject; and (b) administering to thesubject a therapeutically effective amount of a compound of Formula I ora pharmaceutically acceptable salt or solvate thereof. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a cancer cell in a sample obtained from the subject has the FGFRinhibitor resistance mutation corresponding to V561M in SEQ ID NO. 1,V564I or V564F in SEQ ID NO. 3, or V555M in SEQ ID NO. 5; and (d)administering additional doses of the compound of Formula I or apharmaceutically acceptable salt or solvate thereof of step (b) to thesubject as a monotherapy or in conjunction with an additional therapy ortherapeutic agent (e.g., a second FGFR inhibitor, a second compound ofFormula I or a pharmaceutically acceptable salt thereof, orimmunotherapy) or anticancer therapy (e.g., surgery or radiation) if thesubject has a cancer cell that has at least one FGFR inhibitorresistance mutation. In some embodiments, a second FGFR inhibitorselected from the group consisting of ARQ-087, ASP5878, AZD4547, B-701,BAY1179470, BAY1187982, BGJ398, brivanib, Debio 1347, dovitinib, E7090,erdafitinib, FPA144, HMPL-453, INCB054828, lenvatinib, lucitanib,LY3076226, MAX-40279, nintedanib, orantinib, pemigatinib, ponatinib,PRN1371, rogaratinib, sulfatinib, and TAS-120 is administered in step(d). In some embodiments, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting the fusion protein FGFR3-TACC3 in asample from the subject; and (b) administering to the subject atherapeutically effective amount of a compound of Formula I selectedfrom Examples 1-30, or a pharmaceutically acceptable salt or solvatethereof. In some embodiments, the methods further comprise (after (b))(c) determining whether a cancer cell in a sample obtained from thesubject has the FGFR inhibitor resistance mutation corresponding toV561M in SEQ ID NO. 1, V564I or V564F in SEQ ID NO. 3, or V555M in SEQID NO. 5; and (d) administering additional doses of the compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof ofstep (b) to the subject as a monotherapy or in conjunction with anadditional therapy or therapeutic agent (e.g., a second FGFR inhibitor,a second compound of Formula I or a pharmaceutically acceptable saltthereof, or immunotherapy) or anticancer therapy (e.g., surgery orradiation) if the subject has a cancer cell that has at least one FGFRinhibitor resistance mutation. In some embodiments, a second FGFRinhibitor selected from the group consisting of ARQ-087, ASP5878,AZD4547, B-701, BAY1179470, BAY1187982, BGJ398, brivanib, Debio 1347,dovitinib, E7090, erdafitinib, FPA144, HMPL-453, INCB054828, lenvatinib,lucitanib, LY3076226, MAX-40279, nintedanib, orantinib, pemigatinib,ponatinib, PRN1371, rogaratinib, sulfatinib, and TAS-120 is administeredin step (d).

Also, provided herein are methods for treating a FGFR-associated cancerin a subject in need of such treatment, the method comprising (a)detecting a dysregulation of a FGFR gene, a FGFR kinase, or theexpression or activity or level of any of the same in a sample from thesubject; and (b) administering to the subject a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof. In some embodiments, the methodsfurther comprise (after (b)) (c) detecting at least one FGFR inhibitorresistance mutation in a cancer cell in a sample obtained from thesubject; and (d) administering additional doses of the compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof ofstep (b) to the subject as a monotherapy or in conjunction with anadditional therapy or therapeutic agent (e.g., a second FGFR inhibitor,a second compound of Formula I or a pharmaceutically acceptable saltthereof, or immunotherapy) or anticancer therapy (e.g., surgery orradiation). In some embodiments, provided herein are methods fortreating a FGFR-associated cancer in a subject in need of suchtreatment, the method comprising (a) detecting a dysregulation of a FGFRgene, a FGFR kinase, or the expression or activity or level of any ofthe same in a sample from the subject; and (b) administering to thesubject a therapeutically effective amount of a compound of Formula Iselected from Examples 1-30, or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments, the methods further comprise(after (b)) (c) detecting at least one FGFR inhibitor resistancemutation in a cancer cell in a sample obtained from the subject; and (d)administering additional doses of the compound of Formula I or apharmaceutically acceptable salt or solvate thereof of step (b) to thesubject as a monotherapy or in conjunction with an additional therapy ortherapeutic agent (e.g., a second FGFR inhibitor, a second compound ofFormula I or a pharmaceutically acceptable salt thereof, orimmunotherapy) or anticancer therapy (e.g., surgery or radiation). Insome embodiments, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting one or more fusion proteins of Table BAand/or one or more FGFR kinase protein pointmutations/insertions/deletions of Table BC in a sample from the subject;and (b) administering to the subject a therapeutically effective amountof a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof selected from the group consisting of a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the methods further comprise (after (b)) (c) detectingat least one FGFR inhibitor resistance mutation of Table BE in a cancercell in a sample obtained from the subject; and (d) administeringadditional doses of the compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof of step (b) to the subject as amonotherapy or in conjunction with an additional therapy or therapeuticagent (e.g., a second FGFR inhibitor, a second compound of Formula I ora pharmaceutically acceptable salt thereof, or immunotherapy) oranticancer therapy (e.g., surgery or radiation). In some embodiments, asecond FGFR inhibitor selected from the group consisting of ARQ-087,ASP5878, AZD4547, B-701, BAY1179470, BAY1187982, BGJ398, brivanib, Debio1347, dovitinib, E7090, erdafitinib, FPA144, HMPL-453, INCB054828,lenvatinib, lucitanib, LY3076226, MAX-40279, nintedanib, orantinib,pemigatinib, ponatinib, PRN1371, rogaratinib, sulfatinib, and TAS-120 isadministered in step (d). In some embodiments, provided herein aremethods for treating a FGFR-associated cancer in a subject in need ofsuch treatment, the method comprising (a) detecting one or more fusionproteins of Table BA and/or one or more FGFR kinase protein pointmutations/insertions/deletions of Table BC in a sample from the subject;and (b) administering to the subject a therapeutically effective amountof a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof selected from the group consisting of a compound ofFormula I selected from Examples 1-30, or a pharmaceutically acceptablesalt or solvate thereof. In some embodiments, the methods furthercomprise (after (b)) (c) detecting at least one FGFR inhibitorresistance mutation of Table BE in a cancer cell in a sample obtainedfrom the subject; and (d) administering additional doses of the compoundof Formula I or a pharmaceutically acceptable salt or solvate thereof ofstep (b) to the subject as a monotherapy or in conjunction with anadditional therapy or therapeutic agent (e.g., a second FGFR inhibitor,a second compound of Formula I or a pharmaceutically acceptable saltthereof, or immunotherapy) or anticancer therapy (e.g., surgery orradiation). In some embodiments, a second FGFR inhibitor selected fromthe group consisting of ARQ-087, ASP5878, AZD4547, B-701, BAY1179470,BAY1187982, BGJ398, brivanib, Debio 1347, dovitinib, E7090, erdafitinib,FPA144, HMPL-453, INCB054828, lenvatinib, lucitanib, LY3076226,MAX-40279, nintedanib, orantinib, pemigatinib, ponatinib, PRN1371,rogaratinib, sulfatinib, and TAS-120 is administered in step (d). Insome embodiments, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting the fusion protein FGFR3-TACC3 in asample from the subject; and (b) administering to the subject atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the methods further comprise (after (b)) (c) detecting theFGFR inhibitor resistance mutation corresponding to V561M in SEQ ID NO.1, V564I or V564F in SEQ ID NO. 3, or V555M in SEQ ID NO. 5 in a cancercell in a sample obtained from the subject; and (d) administeringadditional doses of the compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof of step (b) to the subject as amonotherapy or in conjunction with an additional therapy or therapeuticagent (e.g., a second FGFR inhibitor, a second compound of Formula I ora pharmaceutically acceptable salt thereof, or immunotherapy) oranticancer therapy (e.g., surgery or radiation). In some embodiments, asecond FGFR inhibitor selected from the group consisting of ARQ-087,ASP5878, AZD4547, B-701, BAY1179470, BAY1187982, BGJ398, brivanib, Debio1347, dovitinib, E7090, erdafitinib, FPA144, HMPL-453, INCB054828,lenvatinib, lucitanib, LY3076226, MAX-40279, nintedanib, orantinib,pemigatinib, ponatinib, PRN1371, rogaratinib, sulfatinib, and TAS-120 isadministered in step (d). In some embodiments, provided herein aremethods for treating a FGFR-associated cancer in a subject in need ofsuch treatment, the method comprising (a) detecting the fusion proteinFGFR3-TACC3 in a sample from the subject; and (b) administering to thesubject a therapeutically effective amount of a compound of Formula Iselected from Examples 1-30, or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments, the methods further comprise(after (b)) (c) detecting the FGFR inhibitor resistance mutationcorresponding to V561M in SEQ ID NO. 1, V564I or V564F in SEQ ID NO. 3,or V555M in SEQ ID NO. 5 in a cancer cell in a sample obtained from thesubject; and (d) administering additional doses of the compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof ofstep (b) to the subject as a monotherapy or in conjunction with anadditional therapy or therapeutic agent (e.g., a second FGFR inhibitor,a second compound of Formula I or a pharmaceutically acceptable saltthereof, or immunotherapy) or anticancer therapy (e.g., surgery orradiation). In some embodiments, a second FGFR inhibitor selected fromthe group consisting of ARQ-087, ASP5878, AZD4547, B-701, BAY1179470,BAY1187982, BGJ398, brivanib, Debio 1347, dovitinib, E7090, erdafitinib,FPA144, HMPL-453, INCB054828, lenvatinib, lucitanib, LY3076226,MAX-40279, nintedanib, orantinib, pemigatinib, ponatinib, PRN1371,rogaratinib, sulfatinib, and TAS-120 is administered in step (d).

Further provided herein is a method for treating bladder cancer in asubject in need thereof, the method comprising administering to thesubject a therapeutically effective amount of a compound of Formula I ora pharmaceutically acceptable salt thereof, crizotinib, osimertinib, orany combination thereof.

As another example, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting a dysregulation of a FGFR gene, a FGFRkinase, or the expression or activity or level of any of the same in asample from the subject; and (b) administering to the subject atherapeutically effective amount of a compound of Formula I, or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a cancer cell in a sample obtained from the subject has at leastone FGFR inhibitor resistance mutation; and (d) administering a secondFGFR inhibitor, wherein the second FGFR inhibitor is selected from thegroup consisting of ARQ-087, ASP5878, AZD4547, B-701, BAY1179470,BAY1187982, BGJ398, brivanib, Debio 1347, dovitinib, E7090, erdafitinib,FPA144, HMPL-453, INCB054828, lenvatinib, lucitanib, LY3076226,MAX-40279, nintedanib, orantinib, pemigatinib, ponatinib, PRN1371,rogaratinib, sulfatinib, and TAS-120, as a monotherapy or in conjunctionwith an additional therapy or therapeutic agent to the subject if thesubject has a cancer cell that has at least one FGFR inhibitorresistance mutation; or (e) administering additional doses of thecompound of Formula I or a pharmaceutically acceptable salt or solvatethereof of step (b) to the subject if the subject has a cancer cell thatdoes not have a FGFR inhibitor resistance mutation. In some embodiments,provided herein are methods for treating a FGFR-associated cancer in asubject in need of such treatment, the method comprising (a) detecting adysregulation of a FGFR gene, a FGFR kinase, or the expression oractivity or level of any of the same in a sample from the subject; and(b) administering to the subject a therapeutically effective amount of acompound of Formula I, or a pharmaceutically acceptable salt or solvatethereof. In some embodiments, the methods further comprise (after (b))(c) determining whether a cancer cell in a sample obtained from thesubject has at least one FGFR inhibitor resistance mutation; and (d)administering a second FGFR inhibitor, wherein the second FGFR inhibitoris selected from the group consisting of ARQ-087, ASP5878, AZD4547,B-701, BAY1179470, BAY1187982, BGJ398, brivanib, Debio 1347, dovitinib,E7090, erdafitinib, FPA144, HMPL-453, INCB054828, lenvatinib, lucitanib,LY3076226, MAX-40279, nintedanib, orantinib, pemigatinib, ponatinib,PRN1371, rogaratinib, sulfatinib, and TAS-120, as a monotherapy or inconjunction with an additional therapy or therapeutic agent to thesubject if the subject has a cancer cell that has at least one FGFRinhibitor resistance mutation; or (e) administering additional doses ofthe compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof of step (b) to the subject if the subject has a cancercell that does not have a FGFR inhibitor resistance mutation. In someembodiments, provided herein are methods for treating a FGFR-associatedcancer in a subject in need of such treatment, the method comprising (a)detecting one or more fusion proteins of Table BA and/or one or moreFGFR kinase protein point mutations/insertions/deletions of Table BC ina sample from the subject; and (b) administering to the subject atherapeutically effective amount of a compound of Formula I, or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a cancer cell in a sample obtained from the subject has at leastone FGFR inhibitor resistance mutation of Table BE; and (d)administering a second FGFR inhibitor, wherein the second FGFR inhibitoris selected from the group consisting of ARQ-087, ASP5878, AZD4547,B-701, BAY1179470, BAY1187982, BGJ398, brivanib, Debio 1347, dovitinib,E7090, erdafitinib, FPA144, HMPL-453, INCB054828, lenvatinib, lucitanib,LY3076226, MAX-40279, nintedanib, orantinib, pemigatinib, ponatinib,PRN1371, rogaratinib, sulfatinib, and TAS-120, as a monotherapy or inconjunction with an additional therapy or therapeutic agent to thesubject if the subject has a cancer cell that has at least one FGFRinhibitor resistance mutation; or (e) administering additional doses ofthe compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof of step (b) to the subject if the subject has a cancercell that does not have a FGFR inhibitor resistance mutation. In someembodiments, provided herein are methods for treating a FGFR-associatedcancer in a subject in need of such treatment, the method comprising (a)detecting the fusion protein FGFR3-TACC3 in a sample from the subject;and (b) administering to the subject a therapeutically effective amountof a compound of Formula I, or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments, the methods further comprise(after (b)) (c) determining whether a cancer cell in a sample obtainedfrom the subject has the FGFR inhibitor resistance mutationcorresponding to V561M in SEQ ID NO. 1, V564I or V564F in SEQ ID NO. 3,or V555M in SEQ ID NO. 5; and (d) administering a second FGFR inhibitor,wherein the second FGFR inhibitor is selected from the group consistingof ARQ-087, ASP5878, AZD4547, B-701, BAY1179470, BAY1187982, BGJ398,brivanib, Debio 1347, dovitinib, E7090, erdafitinib, FPA144, HMPL-453,INCB054828, lenvatinib, lucitanib, LY3076226, MAX-40279, nintedanib,orantinib, pemigatinib, ponatinib, PRN1371, rogaratinib, sulfatinib, andTAS-120, as a monotherapy or in conjunction with an additional therapyor therapeutic agent to the subject if the subject has a cancer cellthat has at least one FGFR inhibitor resistance mutation; or (e)administering additional doses of the compound of Formula I or apharmaceutically acceptable salt or solvate thereof of step (b) to thesubject if the subject has a cancer cell that does not have a FGFRinhibitor resistance mutation. In some of the embodiments of any of themethods described herein, a compound of Formula I can be selected fromthe group consisting of Examples 1-30.

As another example, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting a dysregulation of a FGFR gene, a FGFRkinase, or the expression or activity or level of any of the same in asample from the subject; and (b) administering to the subject atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt thereof. In some embodiments, themethods further comprise (after (b)) (c) determining whether a cancercell in a sample obtained from the subject has at least one FGFRinhibitor resistance mutation; and (d) administering a secondtherapeutic agent, wherein the second therapeutic agent is selected fromthe group consisting of crizotinib and osimertinib, as a monotherapy orin conjunction with a compound of Formula I or a pharmaceuticallyacceptable salt thereof to the subject if the subject has a cancer cellthat has at least one FGFR inhibitor resistance mutation; or (e)administering additional doses of the compound of Formula I or apharmaceutically acceptable salt thereof of step (b) to the subject ifthe subject has a cancer cell that does not have a FGFR inhibitorresistance mutation. In some embodiments, provided herein are methodsfor treating a FGFR-associated cancer in a subject in need of suchtreatment, the method comprising (a) detecting one or more fusionproteins of Table BA and/or one or more FGFR kinase protein pointmutations/insertions of Table BC in a sample from the subject; and (b)administering to the subject a therapeutically effective amount of acompound of Formula I or a pharmaceutically acceptable salt thereof. Insome embodiments, the methods further comprise (after (b)) (c)determining whether a cancer cell in a sample obtained from the subjecthas at least one FGFR inhibitor resistance mutation of Table BE; and (d)administering a second therapeutic agent, wherein the second therapeuticagent is selected from the group consisting of crizotinib andosimertinib, as a monotherapy or in conjunction with a compound ofFormula I or a pharmaceutically acceptable salt thereof to the subjectif the subject has a cancer cell that has at least one FGFR inhibitorresistance mutation; or (e) administering additional doses of thecompound of Formula I or a pharmaceutically acceptable salt thereof ofstep (b) to the subject if the subject has a cancer cell that does nothave a FGFR inhibitor resistance mutation. In some embodiments of theabove, the FGFR-associated cancer is a bladder cancer.

As another example, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting a dysregulation of a FGFR gene, a FGFRkinase, or the expression or activity or level of any of the same in asample from the subject; and (b) administering to the subject atherapeutically effective amount of a compound of Formula I, or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a cancer cell in a sample obtained from the subject has at leastone FGFR inhibitor resistance mutation; and (d) administering amultikinase inhibitor (e.g., brivanib, dasatinib, erdafitinib,lenvatinib, lucitanib, nintedanib, orantinib, ponatinib, or sulfatinib),as a monotherapy or in conjunction with an additional therapy ortherapeutic agent to the subject if the subject has a cancer cell thathas at least one FGFR inhibitor resistance mutation; or (e)administering additional doses of the compound of Formula I or apharmaceutically acceptable salt or solvate thereof of step (b) to thesubject if the subject has a cancer cell that does not have a FGFRinhibitor resistance mutation. In some embodiments, provided herein aremethods for treating a FGFR-associated cancer in a subject in need ofsuch treatment, the method comprising (a) detecting a dysregulation of aFGFR gene, a FGFR kinase, or the expression or activity or level of anyof the same in a sample from the subject; and (b) administering to thesubject a therapeutically effective amount of a compound of Formula Iselected from Examples 1-30, or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments, the methods further comprise(after (b)) (c) determining whether a cancer cell in a sample obtainedfrom the subject has at least one FGFR inhibitor resistance mutation;and (d) administering a multikinase inhibitor (e.g., brivanib,dasatinib, erdafitinib, lenvatinib, lucitanib, nintedanib, orantinib,ponatinib, or sulfatinib), as a monotherapy or in conjunction with anadditional therapy or therapeutic agent to the subject if the subjecthas a cancer cell that has at least one FGFR inhibitor resistancemutation; or (e) administering additional doses of the compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof ofstep (b) to the subject if the subject has a cancer cell that does nothave a FGFR inhibitor resistance mutation. In some embodiments, providedherein are methods for treating a FGFR-associated cancer in a subject inneed of such treatment, the method comprising (a) detecting one or morefusion proteins of Table BA and/or one or more FGFR kinase protein pointmutations/insertions/deletions of Table BC in a sample from the subject;and (b) administering to the subject a therapeutically effective amountof a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments, the methods further comprise(after (b)) (c) determining whether a cancer cell in a sample obtainedfrom the subject has at least one FGFR inhibitor resistance mutation ofTable BE; and (d) administering a multikinase inhibitor (e.g., brivanib,dasatinib, erdafitinib, lenvatinib, lucitanib, nintedanib, orantinib,ponatinib, or sulfatinib), as a monotherapy or in conjunction with anadditional therapy or therapeutic agent to the subject if the subjecthas a cancer cell that has at least one FGFR inhibitor resistancemutation; or (e) administering additional doses of the compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof ofstep (b) to the subject if the subject has a cancer cell that does nothave a FGFR inhibitor resistance mutation. In some embodiments, providedherein are methods for treating a FGFR-associated cancer in a subject inneed of such treatment, the method comprising (a) detecting one or morefusion proteins of Table BA and/or one or more FGFR kinase protein pointmutations/insertions/deletions of Table BC in a sample from the subject;and (b) administering to the subject a therapeutically effective amountof a compound of Formula I selected from Examples 1-30, or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a cancer cell in a sample obtained from the subject has at leastone FGFR inhibitor resistance mutation of Table BE; and (d)administering a multikinase inhibitor (e.g., brivanib, dasatinib,erdafitinib, lenvatinib, lucitanib, nintedanib, orantinib, ponatinib, orsulfatinib), as a monotherapy or in conjunction with an additionaltherapy or therapeutic agent to the subject if the subject has a cancercell that has at least one FGFR inhibitor resistance mutation; or (e)administering additional doses of the compound of Formula I or apharmaceutically acceptable salt or solvate thereof of step (b) to thesubject if the subject has a cancer cell that does not have a FGFRinhibitor resistance mutation. In some embodiments, provided herein aremethods for treating a FGFR-associated cancer in a subject in need ofsuch treatment, the method comprising (a) detecting the fusion proteinFGFR3-TACC3 in a sample from the subject; and (b) administering to thesubject a therapeutically effective amount of a compound of Formula I ora pharmaceutically acceptable salt or solvate thereof. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a cancer cell in a sample obtained from the subject has the FGFRinhibitor resistance mutation corresponding to V561M in SEQ ID NO. 1,V564I or V564F in SEQ ID NO. 3, or V555M in SEQ ID NO. 5; and (d)administering a multikinase inhibitor (e.g., brivanib, dasatinib,erdafitinib, lenvatinib, lucitanib, nintedanib, orantinib, ponatinib, orsulfatinib) as a monotherapy or in conjunction with an additionaltherapy or therapeutic agent to the subject if the subject has a cancercell that has at least one FGFR inhibitor resistance mutation; or (e)administering additional doses of the compound of Formula I or apharmaceutically acceptable salt or solvate thereof of step (b) to thesubject if the subject has a cancer cell that does not have a FGFRinhibitor resistance mutation. In some embodiments, provided herein aremethods for treating a FGFR-associated cancer in a subject in need ofsuch treatment, the method comprising (a) detecting the fusion proteinFGFR3-TACC3 in a sample from the subject; and (b) administering to thesubject a therapeutically effective amount of a compound of Formula Iselected from Examples 1-30, or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments, the methods further comprise(after (b)) (c) determining whether a cancer cell in a sample obtainedfrom the subject has the FGFR inhibitor resistance mutationcorresponding to V561M in SEQ ID NO. 1, V564I or V564F in SEQ ID NO. 3,or V555M in SEQ ID NO. 5; and (d) administering a multikinase inhibitor(e.g., brivanib, dasatinib, erdafitinib, lenvatinib, lucitanib,nintedanib, orantinib, ponatinib, or sulfatinib) as a monotherapy or inconjunction with an additional therapy or therapeutic agent to thesubject if the subject has a cancer cell that has at least one FGFRinhibitor resistance mutation; or (e) administering additional doses ofthe compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof of step (b) to the subject if the subject has a cancercell that does not have a FGFR inhibitor resistance mutation.

In some embodiments, the presence of one or more FGFR inhibitorresistance mutations in a cysteine in a tumor causes the tumor to bemore resistant to treatment with a compound of Formula I or apharmaceutically acceptable salt or solvate thereof. Methods useful whena FGFR inhibitor resistance mutation in a cysteine causes the tumor tobe more resistant to treatment with a compound of Formula I or apharmaceutically acceptable salt or solvate thereof are described below.For example, provided herein are methods of treating a subject having acancer that include: identifying a subject having a cancer cell that hasone or more FGFR inhibitor resistance mutations in a cysteine; andadministering to the identified subject a treatment that does notinclude a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof as a monotherapy or in conjunction with an additionaltherapy or therapeutic agent (e.g., a second FGFR kinase inhibitor).Also provided are methods of treating a subject identified as having acancer cell that has one or more FGFR inhibitor resistance mutations ina cysteine that include administering to the subject a treatment thatdoes not include a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof as a monotherapy or in conjunctionwith an additional therapy or therapeutic agent (e.g., a second FGFRkinase inhibitor). In some embodiments, the one or more FGFR inhibitorresistance mutations in a cysteine confer increased resistance to acancer cell or tumor to treatment with a compound of Formula I or apharmaceutically acceptable salt or solvate thereof.

Also provided are methods of treating a subject having a cancer thatinclude: (a) administering one or more doses of a compound of Formula Ior a pharmaceutically acceptable salt or solvate thereof for a period oftime; (b) after (a), determining whether a cancer cell in a sampleobtained from the subject has one or more FGFR inhibitor resistancemutations in a cysteine; and (c) administering a second FGFR inhibitoror a second compound of Formula I or a pharmaceutically acceptable saltor solvate thereof as a monotherapy or in conjunction with an additionaltherapy or therapeutic agent to a subject having a cancer cell that hasone or more FGFR inhibitor resistance mutations in a cysteine; or (d)administering additional doses of the compound of Formula I or apharmaceutically acceptable salt or solvate thereof of step (a) to asubject having a cancer cell that does not have a FGFR inhibitorresistance mutation in a cysteine. In some embodiments, where thesubject is administered additional doses of the compound of Formula I ora pharmaceutically acceptable salt or solvate thereof of step (a), thesubject can also be administered an additional therapy or therapeuticagent or a second compound of Formula I or a pharmaceutically acceptablesalt or solvate thereof. In some embodiments, the one or more FGFRinhibitor resistance mutations in a cysteine confer increased resistanceto a cancer cell or tumor to treatment with a compound of Formula I or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the additional therapy or therapeutic agent is anyanticancer agent known in the art. For example, the additional therapyor therapeutic agent is another FGFR inhibitor (e.g., a second FGFRinhibitor). In some embodiments, the additional therapy or therapeuticagent is an immunotherapy. In some embodiments, another FGFR inhibitorcan be the compound of Formula I or a pharmaceutically acceptable saltor solvate thereof administered in step (a).

Also provided are methods of treating a subject having a cancer thatinclude: (a) determining whether a cancer cell in a sample obtained froma subject having a cancer and previously administered one or more dosesof a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof, has one or more FGFR inhibitor resistance mutations ina cysteine; (b) administering a second FGFR inhibitor or a secondcompound of Formula I or a pharmaceutically acceptable salt or solvatethereof as a monotherapy or in conjunction with an additional therapy ortherapeutic agent to a subject having a cancer cell that has one or moreFGFR inhibitor resistance mutations in a cysteine; or (c) administeringadditional doses of the compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof previously administered to a subjecthaving a cancer cell that does not have a FGFR inhibitor resistancemutation in a cysteine. In some embodiments, where the subject isadministered additional doses of the compound of Formula I or apharmaceutically acceptable salt or solvate thereof of step (a), thesubject can also be administered an additional therapy or therapeuticagent. In some embodiments, the one or more FGFR inhibitor resistancemutations in a cysteine confer increased resistance to a cancer cell ortumor to treatment with a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof. In some embodiments, the additionaltherapy or therapeutic agent is any anticancer agent known in the art.For example, the additional therapy or therapeutic agent is another FGFRinhibitor (e.g., a second FGFR inhibitor). In some embodiments, theadditional therapy or therapeutic agent is an immunotherapy. In someembodiments, another FGFR inhibitor can be the compound of Formula I ora pharmaceutically acceptable salt or solvate thereof administered instep (a).

In some embodiments of any of the methods described herein, a FGFRinhibitor resistance mutation in a cysteine that confers increasedresistance to a cancer cell or tumor to treatment with a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof, canbe a mutation in a cysteine corresponding to Cys582 in SEQ ID NO: 5. Insome embodiments of any of the methods described herein, a FGFRinhibitor resistance mutation in a cysteine that confers increasedresistance to a cancer cell or tumor to treatment with a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof, canbe a mutation in a cysteine corresponding to Cys790 in SEQ ID NO: 3.

Also, provided herein are methods for treating a FGFR-associated cancerin a subject in need of such treatment, the method comprising (a)detecting a dysregulation of a FGFR gene, a FGFR kinase, or theexpression or activity or level of any of the same in a sample from thesubject; and (b) administering to the subject a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof. In some embodiments, the methodsfurther comprise (after (b)) (c) determining whether a cancer cell in asample obtained from the subject has at least one FGFR inhibitorresistance mutation in a cysteine; and (d) administering additionaldoses of the compound of Formula I or a pharmaceutically acceptable saltor solvate thereof of step (b) to the subject as a monotherapy or inconjunction with an additional therapy or therapeutic agent (e.g., asecond FGFR inhibitor, a second compound of Formula I or apharmaceutically acceptable salt thereof, or immunotherapy) oranticancer therapy (e.g., surgery or radiation) if the subject has acancer cell that has at least one FGFR inhibitor resistance mutation ina cysteine. Also, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting a dysregulation of a FGFR gene, a FGFRkinase, or the expression or activity or level of any of the same in asample from the subject; and (b) administering to the subject atherapeutically effective amount of a compound of Formula I selectedfrom the group consisting of Examples 1-30 or a pharmaceuticallyacceptable salt or solvate thereof. In some embodiments, the methodsfurther comprise (after (b)) (c) determining whether a cancer cell in asample obtained from the subject has at least one FGFR inhibitorresistance mutation in a cysteine; and (d) administering additionaldoses of the compound of Formula I or a pharmaceutically acceptable saltor solvate thereof of step (b) to the subject as a monotherapy or inconjunction with an additional therapy or therapeutic agent (e.g., asecond FGFR inhibitor, a second compound of Formula I or apharmaceutically acceptable salt thereof, or immunotherapy) oranticancer therapy (e.g., surgery or radiation) if the subject has acancer cell that has at least one FGFR inhibitor resistance mutation ina cysteine. In some embodiments, provided herein are methods fortreating a FGFR-associated cancer in a subject in need of suchtreatment, the method comprising (a) detecting one or more fusionproteins of Table BA and/or one or more FGFR kinase protein pointmutations/insertions/deletions of Table BC in a sample from the subject;and (b) administering to the subject a therapeutically effective amountof a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof selected from the group consisting of a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the methods further comprise (after (b)) (c)determining whether a cancer cell in a sample obtained from the subjecthas at least one FGFR inhibitor resistance mutation in a cysteine; and(d) administering additional doses of the compound of Formula I or apharmaceutically acceptable salt or solvate thereof of step (b) to thesubject as a monotherapy or in conjunction with an additional therapy ortherapeutic agent (e.g., a second FGFR inhibitor, a second compound ofFormula I or a pharmaceutically acceptable salt thereof, orimmunotherapy) or anticancer therapy (e.g., surgery or radiation) if thesubject has a cancer cell that has at least one FGFR inhibitorresistance mutation in a cysteine. In some embodiments, a second FGFRinhibitor selected from the group consisting of ARQ-087, ASP5878,AZD4547, B-701, BAY1179470, BAY1187982, BGJ398, brivanib, Debio 1347,dovitinib, E7090, erdafitinib, FPA144, HMPL-453, INCB054828, lenvatinib,lucitanib, LY3076226, MAX-40279, nintedanib, orantinib, pemigatinib,ponatinib, PRN1371, rogaratinib, sulfatinib, and TAS-120 is administeredin step (d). In some embodiments, provided herein are methods fortreating a FGFR-associated cancer in a subject in need of suchtreatment, the method comprising (a) detecting one or more fusionproteins of Table BA and/or one or more FGFR kinase protein pointmutations/insertions/deletions of Table BC in a sample from the subject;and (b) administering to the subject a therapeutically effective amountof a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof selected from the group consisting of a compound ofFormula I selected from Examples 1-30, or a pharmaceutically acceptablesalt or solvate thereof. In some embodiments, the methods furthercomprise (after (b)) (c) determining whether a cancer cell in a sampleobtained from the subject has at least one FGFR inhibitor resistancemutation in a cysteine; and (d) administering additional doses of thecompound of Formula I or a pharmaceutically acceptable salt or solvatethereof of step (b) to the subject as a monotherapy or in conjunctionwith an additional therapy or therapeutic agent (e.g., a second FGFRinhibitor, a second compound of Formula I or a pharmaceuticallyacceptable salt thereof, or immunotherapy) or anticancer therapy (e.g.,surgery or radiation) if the subject has a cancer cell that has at leastone FGFR inhibitor resistance mutation in a cysteine. In someembodiments, a second FGFR inhibitor selected from the group consistingof ARQ-087, ASP5878, AZD4547, B-701, BAY1179470, BAY1187982, BGJ398,brivanib, Debio 1347, dovitinib, E7090, erdafitinib, FPA144, HMPL-453,INCB054828, lenvatinib, lucitanib, LY3076226, MAX-40279, nintedanib,orantinib, pemigatinib, ponatinib, PRN1371, rogaratinib, sulfatinib, andTAS-120 is administered in step (d). In some embodiments, providedherein are methods for treating a FGFR-associated cancer in a subject inneed of such treatment, the method comprising (a) detecting the fusionprotein FGFR3-TACC3 in a sample from the subject; and (b) administeringto the subject a therapeutically effective amount of a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the methods further comprise (after (b)) (c)determining whether a cancer cell in a sample obtained from the subjecthas the FGFR inhibitor resistance mutation in a cysteine correspondingto Cys582 of SEQ ID NO: 5 or a cysteine corresponding to Cys790 of SEQID NO:3; and (d) administering additional doses of the compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof ofstep (b) to the subject as a monotherapy or in conjunction with anadditional therapy or therapeutic agent (e.g., a second FGFR inhibitor,a second compound of Formula I or a pharmaceutically acceptable saltthereof, or immunotherapy) or anticancer therapy (e.g., surgery orradiation) if the subject has a cancer cell that has at least one FGFRinhibitor resistance mutation in a cysteine. In some embodiments, asecond FGFR inhibitor selected from the group consisting of ARQ-087,ASP5878, AZD4547, B-701, BAY1179470, BAY1187982, BGJ398, brivanib, Debio1347, dovitinib, E7090, erdafitinib, FPA144, HMPL-453, INCB054828,lenvatinib, lucitanib, LY3076226, MAX-40279, nintedanib, orantinib,pemigatinib, ponatinib, PRN1371, rogaratinib, sulfatinib, and TAS-120 isadministered in step (d). In some embodiments, provided herein aremethods for treating a FGFR-associated cancer in a subject in need ofsuch treatment, the method comprising (a) detecting the fusion proteinFGFR3-TACC3 in a sample from the subject; and (b) administering to thesubject a therapeutically effective amount of a compound of Formula Iselected from Examples 1-30, or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments, the methods further comprise(after (b)) (c) determining whether a cancer cell in a sample obtainedfrom the subject has the FGFR inhibitor resistance mutation in acysteine corresponding to Cys582 of SEQ ID NO: 5 or a cysteinecorresponding to Cys790 of SEQ ID NO:3; and (d) administering additionaldoses of the compound of Formula I or a pharmaceutically acceptable saltor solvate thereof of step (b) to the subject as a monotherapy or inconjunction with an additional therapy or therapeutic agent (e.g., asecond FGFR inhibitor, a second compound of Formula I or apharmaceutically acceptable salt thereof, or immunotherapy) oranticancer therapy (e.g., surgery or radiation) if the subject has acancer cell that has at least one FGFR inhibitor resistance mutation ina cysteine. In some embodiments, a second FGFR inhibitor selected fromthe group consisting of ARQ-087, ASP5878, AZD4547, B-701, BAY1179470,BAY1187982, BGJ398, brivanib, Debio 1347, dovitinib, E7090, erdafitinib,FPA144, HMPL-453, INCB054828, lenvatinib, lucitanib, LY3076226,MAX-40279, nintedanib, orantinib, pemigatinib, ponatinib, PRN1371,rogaratinib, sulfatinib, and TAS-120 is administered in step (d).

Also, provided herein are methods for treating a FGFR-associated cancerin a subject in need of such treatment, the method comprising (a)detecting a dysregulation of a FGFR gene, a FGFR kinase, or theexpression or activity or level of any of the same in a sample from thesubject; and (b) administering to the subject a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof. In some embodiments, the methodsfurther comprise (after (b)) (c) detecting at least one FGFR inhibitorresistance mutation in a cysteine in a cancer cell in a sample obtainedfrom the subject; and (d) administering additional doses of the compoundof Formula I or a pharmaceutically acceptable salt or solvate thereof ofstep (b) to the subject as a monotherapy or in conjunction with anadditional therapy or therapeutic agent (e.g., a second FGFR inhibitor,a second compound of Formula I or a pharmaceutically acceptable saltthereof, or immunotherapy) or anticancer therapy (e.g., surgery orradiation). In some embodiments, provided herein are methods fortreating a FGFR-associated cancer in a subject in need of suchtreatment, the method comprising (a) detecting a dysregulation of a FGFRgene, a FGFR kinase, or the expression or activity or level of any ofthe same in a sample from the subject; and (b) administering to thesubject a therapeutically effective amount of a compound of Formula Iselected from Examples 1-30, or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments, the methods further comprise(after (b)) (c) detecting at least one FGFR inhibitor resistancemutation in a cysteine in a cancer cell in a sample obtained from thesubject; and (d) administering additional doses of the compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof ofstep (b) to the subject as a monotherapy or in conjunction with anadditional therapy or therapeutic agent (e.g., a second FGFR inhibitor,a second compound of Formula I or a pharmaceutically acceptable saltthereof, or immunotherapy) or anticancer therapy (e.g., surgery orradiation). In some embodiments, provided herein are methods fortreating a FGFR-associated cancer in a subject in need of suchtreatment, the method comprising (a) detecting one or more fusionproteins of Table BA and/or one or more FGFR kinase protein pointmutations/insertions/deletions of Table BC in a sample from the subject;and (b) administering to the subject a therapeutically effective amountof a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof selected from the group consisting of a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the methods further comprise (after (b)) (c) detectingat least one FGFR inhibitor resistance mutation in a cysteine in acancer cell in a sample obtained from the subject; and (d) administeringadditional doses of the compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof of step (b) to the subject as amonotherapy or in conjunction with an additional therapy or therapeuticagent (e.g., a second FGFR inhibitor, a second compound of Formula I ora pharmaceutically acceptable salt thereof, or immunotherapy) oranticancer therapy (e.g., surgery or radiation). In some embodiments, asecond FGFR inhibitor selected from the group consisting of ARQ-087,ASP5878, AZD4547, B-701, BAY1179470, BAY1187982, BGJ398, brivanib, Debio1347, dovitinib, E7090, erdafitinib, FPA144, HMPL-453, INCB054828,lenvatinib, lucitanib, LY3076226, MAX-40279, nintedanib, orantinib,pemigatinib, ponatinib, PRN1371, rogaratinib, sulfatinib, and TAS-120 isadministered in step (d). In some embodiments, provided herein aremethods for treating a FGFR-associated cancer in a subject in need ofsuch treatment, the method comprising (a) detecting one or more fusionproteins of Table BA and/or one or more FGFR kinase protein pointmutations/insertions/deletions of Table BC in a sample from the subject;and (b) administering to the subject a therapeutically effective amountof a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof selected from the group consisting of a compound ofFormula I selected from Examples 1-30, or a pharmaceutically acceptablesalt or solvate thereof. In some embodiments, the methods furthercomprise (after (b)) (c) detecting at least one FGFR inhibitorresistance mutation in a cysteine in a cancer cell in a sample obtainedfrom the subject; and (d) administering additional doses of the compoundof Formula I or a pharmaceutically acceptable salt or solvate thereof ofstep (b) to the subject as a monotherapy or in conjunction with anadditional therapy or therapeutic agent (e.g., a second FGFR inhibitor,a second compound of Formula I or a pharmaceutically acceptable saltthereof, or immunotherapy) or anticancer therapy (e.g., surgery orradiation). In some embodiments, a second FGFR inhibitor selected fromthe group consisting of ARQ-087, ASP5878, AZD4547, B-701, BAY1179470,BAY1187982, BGJ398, brivanib, Debio 1347, dovitinib, E7090, erdafitinib,FPA144, HMPL-453, INCB054828, lenvatinib, lucitanib, LY3076226,MAX-40279, nintedanib, orantinib, pemigatinib, ponatinib, PRN1371,rogaratinib, sulfatinib, and TAS-120 is administered in step (d). Insome embodiments, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting the fusion protein FGFR3-TACC3 in asample from the subject; and (b) administering to the subject atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the methods further comprise (after (b)) (c) detecting theFGFR inhibitor resistance mutation in a cysteine corresponding to Cys582of SEQ ID NO: 5 or a cysteine corresponding to Cys790 of SEQ ID NO:3 ina cancer cell in a sample obtained from the subject; and (d)administering additional doses of the compound of Formula I or apharmaceutically acceptable salt or solvate thereof of step (b) to thesubject as a monotherapy or in conjunction with an additional therapy ortherapeutic agent (e.g., a second FGFR inhibitor, a second compound ofFormula I or a pharmaceutically acceptable salt thereof, orimmunotherapy) or anticancer therapy (e.g., surgery or radiation). Insome embodiments, a second FGFR inhibitor selected from the groupconsisting of ARQ-087, ASP5878, AZD4547, B-701, BAY1179470, BAY1187982,BGJ398, brivanib, Debio 1347, dovitinib, E7090, erdafitinib, FPA144,HMPL-453, INCB054828, lenvatinib, lucitanib, LY3076226, MAX-40279,nintedanib, orantinib, pemigatinib, ponatinib, PRN1371, rogaratinib,sulfatinib, and TAS-120 is administered in step (d). In someembodiments, provided herein are methods for treating a FGFR-associatedcancer in a subject in need of such treatment, the method comprising (a)detecting the fusion protein FGFR3-TACC3 in a sample from the subject;and (b) administering to the subject a therapeutically effective amountof a compound of Formula I selected from Examples 1-30, or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the methods further comprise (after (b)) (c) detecting theFGFR inhibitor resistance mutation in a cysteine corresponding to Cys582of SEQ ID NO: 5 or a cysteine corresponding to Cys790 of SEQ ID NO:3 ina cancer cell in a sample obtained from the subject; and (d)administering additional doses of the compound of Formula I or apharmaceutically acceptable salt or solvate thereof of step (b) to thesubject as a monotherapy or in conjunction with an additional therapy ortherapeutic agent (e.g., a second FGFR inhibitor, a second compound ofFormula I or a pharmaceutically acceptable salt thereof, orimmunotherapy) or anticancer therapy (e.g., surgery or radiation). Insome embodiments, a second FGFR inhibitor selected from the groupconsisting of ARQ-087, ASP5878, AZD4547, B-701, BAY1179470, BAY1187982,BGJ398, brivanib, Debio 1347, dovitinib, E7090, erdafitinib, FPA144,HMPL-453, INCB054828, lenvatinib, lucitanib, LY3076226, MAX-40279,nintedanib, orantinib, pemigatinib, ponatinib, PRN1371, rogaratinib,sulfatinib, and TAS-120 is administered in step (d).

As another example, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting a dysregulation of a FGFR gene, a FGFRkinase, or the expression or activity or level of any of the same in asample from the subject; and (b) administering to the subject atherapeutically effective amount of a compound of Formula I, or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a cancer cell in a sample obtained from the subject has at leastone FGFR inhibitor resistance mutation in a cysteine; and (d)administering a second FGFR inhibitor, wherein the second FGFR inhibitoris selected from the group consisting of ARQ-087, ASP5878, AZD4547,B-701, BAY1179470, BAY1187982, BGJ398, brivanib, Debio 1347, dovitinib,E7090, erdafitinib, FPA144, HMPL-453, INCB054828, lenvatinib, lucitanib,LY3076226, MAX-40279, nintedanib, orantinib, pemigatinib, ponatinib,PRN1371, rogaratinib, sulfatinib, and TAS-120, as a monotherapy or inconjunction with an additional therapy or therapeutic agent to thesubject if the subject has a cancer cell that has at least one FGFRinhibitor resistance mutation in a cysteine; or (e) administeringadditional doses of the compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof of step (b) to the subject if thesubject has a cancer cell that does not have a FGFR inhibitor resistancemutation in a cysteine. In some embodiments, provided herein are methodsfor treating a FGFR-associated cancer in a subject in need of suchtreatment, the method comprising (a) detecting a dysregulation of a FGFRgene, a FGFR kinase, or the expression or activity or level of any ofthe same in a sample from the subject; and (b) administering to thesubject a therapeutically effective amount of a compound of Formula I,or a pharmaceutically acceptable salt or solvate thereof. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a cancer cell in a sample obtained from the subject has at leastone FGFR inhibitor resistance mutation in a cysteine; and (d)administering a second FGFR inhibitor, wherein the second FGFR inhibitoris selected from the group consisting of ARQ-087, ASP5878, AZD4547,B-701, BAY1179470, BAY1187982, BGJ398, brivanib, Debio 1347, dovitinib,E7090, erdafitinib, FPA144, HMPL-453, INCB054828, lenvatinib, lucitanib,LY3076226, MAX-40279, nintedanib, orantinib, pemigatinib, ponatinib,PRN1371, rogaratinib, sulfatinib, and TAS-120, as a monotherapy or inconjunction with an additional therapy or therapeutic agent to thesubject if the subject has a cancer cell that has at least one FGFRinhibitor resistance mutation in a cysteine; or (e) administeringadditional doses of the compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof of step (b) to the subject if thesubject has a cancer cell that does not have a FGFR inhibitor resistancemutation in a cysteine. In some embodiments, provided herein are methodsfor treating a FGFR-associated cancer in a subject in need of suchtreatment, the method comprising (a) detecting one or more fusionproteins of Table BA and/or one or more FGFR kinase protein pointmutations/insertions/deletions of Table BC in a sample from the subject;and (b) administering to the subject a therapeutically effective amountof a compound of Formula I, or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments, the methods further comprise(after (b)) (c) determining whether a cancer cell in a sample obtainedfrom the subject has at least one FGFR inhibitor resistance mutation ina cysteine; and (d) administering a second FGFR inhibitor, wherein thesecond FGFR inhibitor is selected from the group consisting of ARQ-087,ASP5878, AZD4547, B-701, BAY1179470, BAY1187982, BGJ398, brivanib, Debio1347, dovitinib, E7090, erdafitinib, FPA144, HMPL-453, INCB054828,lenvatinib, lucitanib, LY3076226, MAX-40279, nintedanib, orantinib,pemigatinib, ponatinib, PRN1371, rogaratinib, sulfatinib, and TAS-120,as a monotherapy or in conjunction with an additional therapy ortherapeutic agent to the subject if the subject has a cancer cell thathas at least one FGFR inhibitor resistance mutation in a cysteine; or(e) administering additional doses of the compound of Formula I or apharmaceutically acceptable salt or solvate thereof of step (b) to thesubject if the subject has a cancer cell that does not have a FGFRinhibitor resistance mutation in a cysteine. In some embodiments,provided herein are methods for treating a FGFR-associated cancer in asubject in need of such treatment, the method comprising (a) detectingthe fusion protein FGFR3-TACC3 in a sample from the subject; and (b)administering to the subject a therapeutically effective amount of acompound of Formula I, or a pharmaceutically acceptable salt or solvatethereof. In some embodiments, the methods further comprise (after (b))(c) determining whether a cancer cell in a sample obtained from thesubject has the FGFR inhibitor resistance mutation in a cysteinecorresponding to Cys582 of SEQ ID NO: 5 or a cysteine corresponding toCys790 of SEQ ID NO:3; and (d) administering a second FGFR inhibitor,wherein the second FGFR inhibitor is selected from the group consistingof ARQ-087, ASP5878, AZD4547, B-701, BAY1179470, BAY1187982, BGJ398,brivanib, Debio 1347, dovitinib, E7090, erdafitinib, FPA144, HMPL-453,INCB054828, lenvatinib, lucitanib, LY3076226, MAX-40279, nintedanib,orantinib, pemigatinib, ponatinib, PRN1371, rogaratinib, sulfatinib, andTAS-120, as a monotherapy or in conjunction with an additional therapyor therapeutic agent to the subject if the subject has a cancer cellthat has at least one FGFR inhibitor resistance mutation in a cysteine;or (e) administering additional doses of the compound of Formula I or apharmaceutically acceptable salt or solvate thereof of step (b) to thesubject if the subject has a cancer cell that does not have a FGFRinhibitor resistance mutation in a cysteine. In some of the embodimentsof any of the methods described herein, a compound of Formula I can beselected from the group consisting of Examples 1-30.

As another example, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting a dysregulation of a FGFR gene, a FGFRkinase, or the expression or activity or level of any of the same in asample from the subject; and (b) administering to the subject atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt thereof. In some embodiments, themethods further comprise (after (b)) (c) determining whether a cancercell in a sample obtained from the subject has at least one FGFRinhibitor resistance mutation in a cysteine; and (d) administering asecond therapeutic agent, wherein the second therapeutic agent isselected from the group consisting of crizotinib and osimertinib, as amonotherapy or in conjunction with a compound of Formula I or apharmaceutically acceptable salt thereof to the subject if the subjecthas a cancer cell that has at least one FGFR inhibitor resistancemutation in a cysteine; or (e) administering additional doses of thecompound of Formula I or a pharmaceutically acceptable salt thereof ofstep (b) to the subject if the subject has a cancer cell that does nothave a FGFR inhibitor resistance mutation in a cysteine. In someembodiments, provided herein are methods for treating a FGFR-associatedcancer in a subject in need of such treatment, the method comprising (a)detecting one or more fusion proteins of Table BA and/or one or moreFGFR kinase protein point mutations/insertions of Table BC in a samplefrom the subject; and (b) administering to the subject a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt thereof. In some embodiments, the methods furthercomprise (after (b)) (c) determining whether a cancer cell in a sampleobtained from the subject has at least one FGFR inhibitor resistancemutation in a cysteine; and (d) administering a second therapeuticagent, wherein the second therapeutic agent is selected from the groupconsisting of crizotinib and osimertinib, as a monotherapy or inconjunction with a compound of Formula I or a pharmaceuticallyacceptable salt thereof to the subject if the subject has a cancer cellthat has at least one FGFR inhibitor resistance mutation in a cysteine;or (e) administering additional doses of the compound of Formula I or apharmaceutically acceptable salt thereof of step (b) to the subject ifthe subject has a cancer cell that does not have a FGFR inhibitorresistance mutation in a cysteine. In some embodiments of the above, theFGFR-associated cancer is a bladder cancer.

As another example, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting a dysregulation of a FGFR gene, a FGFRkinase, or the expression or activity or level of any of the same in asample from the subject; and (b) administering to the subject atherapeutically effective amount of a compound of Formula I, or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a cancer cell in a sample obtained from the subject has at leastone FGFR inhibitor resistance mutation in a cysteine; and (d)administering a multikinase inhibitor (e.g., brivanib, dasatinib,erdafitinib, lenvatinib, lucitanib, nintedanib, orantinib, ponatinib, orsulfatinib), as a monotherapy or in conjunction with an additionaltherapy or therapeutic agent to the subject if the subject has a cancercell that has at least one FGFR inhibitor resistance mutation in acysteine; or (e) administering additional doses of the compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof ofstep (b) to the subject if the subject has a cancer cell that does nothave a FGFR inhibitor resistance mutation in a cysteine. In someembodiments, provided herein are methods for treating a FGFR-associatedcancer in a subject in need of such treatment, the method comprising (a)detecting a dysregulation of a FGFR gene, a FGFR kinase, or theexpression or activity or level of any of the same in a sample from thesubject; and (b) administering to the subject a therapeuticallyeffective amount of a compound of Formula I selected from Examples 1-30,or a pharmaceutically acceptable salt or solvate thereof. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a cancer cell in a sample obtained from the subject has at leastone FGFR inhibitor resistance mutation in a cysteine; and (d)administering a multikinase inhibitor (e.g., brivanib, dasatinib,erdafitinib, lenvatinib, lucitanib, nintedanib, orantinib, ponatinib, orsulfatinib), as a monotherapy or in conjunction with an additionaltherapy or therapeutic agent to the subject if the subject has a cancercell that has at least one FGFR inhibitor resistance mutation in acysteine; or (e) administering additional doses of the compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof ofstep (b) to the subject if the subject has a cancer cell that does nothave a FGFR inhibitor resistance mutation in a cysteine. In someembodiments, provided herein are methods for treating a FGFR-associatedcancer in a subject in need of such treatment, the method comprising (a)detecting one or more fusion proteins of Table BA and/or one or moreFGFR kinase protein point mutations/insertions/deletions of Table BC ina sample from the subject; and (b) administering to the subject atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a cancer cell in a sample obtained from the subject has at leastone FGFR inhibitor resistance mutation in a cysteine; and (d)administering a multikinase inhibitor (e.g., brivanib, dasatinib,erdafitinib, lenvatinib, lucitanib, nintedanib, orantinib, ponatinib, orsulfatinib), as a monotherapy or in conjunction with an additionaltherapy or therapeutic agent to the subject if the subject has a cancercell that has at least one FGFR inhibitor resistance mutation in acysteine; or (e) administering additional doses of the compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof ofstep (b) to the subject if the subject has a cancer cell that does nothave a FGFR inhibitor resistance mutation in a cysteine. In someembodiments, provided herein are methods for treating a FGFR-associatedcancer in a subject in need of such treatment, the method comprising (a)detecting one or more fusion proteins of Table BA and/or one or moreFGFR kinase protein point mutations/insertions/deletions of Table BC ina sample from the subject; and (b) administering to the subject atherapeutically effective amount of a compound of Formula I selectedfrom Examples 1-30, or a pharmaceutically acceptable salt or solvatethereof. In some embodiments, the methods further comprise (after (b))(c) determining whether a cancer cell in a sample obtained from thesubject has at least one FGFR inhibitor resistance mutation in acysteine; and (d) administering a multikinase inhibitor (e.g., brivanib,dasatinib, erdafitinib, lenvatinib, lucitanib, nintedanib, orantinib,ponatinib, or sulfatinib), as a monotherapy or in conjunction with anadditional therapy or therapeutic agent to the subject if the subjecthas a cancer cell that has at least one FGFR inhibitor resistancemutation in a cysteine; or (e) administering additional doses of thecompound of Formula I or a pharmaceutically acceptable salt or solvatethereof of step (b) to the subject if the subject has a cancer cell thatdoes not have a FGFR inhibitor resistance mutation in a cysteine. Insome embodiments, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting the fusion protein FGFR3-TACC3 in asample from the subject; and (b) administering to the subject atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a cancer cell in a sample obtained from the subject has the FGFRinhibitor resistance mutation in a cysteine corresponding to Cys582 ofSEQ ID NO: 5 or a cysteine corresponding to Cys790 of SEQ ID NO:3; and(d) administering a multikinase inhibitor (e.g., brivanib, dasatinib,erdafitinib, lenvatinib, lucitanib, nintedanib, orantinib, ponatinib, orsulfatinib) as a monotherapy or in conjunction with an additionaltherapy or therapeutic agent to the subject if the subject has a cancercell that has at least one FGFR inhibitor resistance mutation in acysteine; or (e) administering additional doses of the compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof ofstep (b) to the subject if the subject has a cancer cell that does nothave a FGFR inhibitor resistance mutation in a cysteine. In someembodiments, provided herein are methods for treating a FGFR-associatedcancer in a subject in need of such treatment, the method comprising (a)detecting the fusion protein FGFR3-TACC3 in a sample from the subject;and (b) administering to the subject a therapeutically effective amountof a compound of Formula I selected from Examples 1-30, or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a cancer cell in a sample obtained from the subject has the FGFRinhibitor resistance mutation in a cysteine corresponding to Cys582 ofSEQ ID NO: 5 or a cysteine corresponding to Cys790 of SEQ ID NO:3; and(d) administering a multikinase inhibitor (e.g., brivanib, dasatinib,erdafitinib, lenvatinib, lucitanib, nintedanib, orantinib, ponatinib, orsulfatinib) as a monotherapy or in conjunction with an additionaltherapy or therapeutic agent to the subject if the subject has a cancercell that has at least one FGFR inhibitor resistance mutation in acysteine; or (e) administering additional doses of the compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof ofstep (b) to the subject if the subject has a cancer cell that does nothave a FGFR inhibitor resistance mutation in a cysteine.

Also provided are methods of selecting a treatment for a subject havinga cancer that include: identifying a subject having a cancer cell thathas one or more FGFR inhibitor resistance mutations; and selecting atreatment that includes administration of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the one or more FGFR inhibitor resistance mutations conferincreased resistance to a cancer cell or tumor to treatment with a firstFGFR inhibitor. In some embodiments, the compound of Formula I or apharmaceutically acceptable salt or solvate thereof is administered incombination with the first FGFR inhibitor. Also provided are methods ofselecting a treatment for a subject having a cancer that include:selecting a treatment that includes administration of a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof for asubject identified as having a cancer cell that has one or more FGFRinhibitor resistance mutations. Also provided are methods of selecting asubject having a cancer for a treatment that does not include a firstFGFR inhibitor as a monotherapy that include: identifying a subjecthaving a cancer cell that has one or more FGFR inhibitor resistancemutations; and selecting the identified subject for a treatment thatincludes a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof. Also provided are methods of selecting a subjecthaving a cancer for a treatment that does not include a first FGFRinhibitor as a monotherapy that include: selecting a subject identifiedas having a cancer cell that has one or more FGFR inhibitor resistancemutations for a treatment that includes administration of a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the one or more FGFR inhibitor resistance mutationsinclude one or more FGFR inhibitor resistance mutations listed in TableBE. In some embodiments, the one or more FGFR inhibitor resistancemutations can include a substitution at an amino acid positioncorresponding to amino acid position 561 in SEQ ID NO. 1 (e.g., V561M),amino acid position 564 in SEQ ID NO. 3 (e.g., V564I or V564F), or aminoacid position 555 in SEQ ID NO. 5 (e.g., V555M).

Also provided are methods of determining the likelihood that a subjecthaving a cancer (e.g., a FGFR-associated cancer) will have a positiveresponse to treatment with a first FGFR inhibitor as a monotherapy thatinclude: determining whether a cancer cell in a sample obtained from thesubject has one or more FGFR inhibitor resistance mutations; anddetermining that a subject having a cancer cell that has one or moreFGFR inhibitor resistance mutations has a decreased likelihood of havinga positive response (i.e. an increased likelihood of having a negativeresponse) to treatment with a first FGFR inhibitor as a monotherapy.Also provided are methods of determining the likelihood that a subjecthaving a cancer (e.g., a FGFR-associated cancer) will have a positiveresponse to treatment with a first FGFR inhibitor as a monotherapy thatinclude: determining whether a cancer cell in a sample obtained from thesubject has one or more FGFR inhibitor resistance mutations; anddetermining that a subject not having a cancer cell that has one or moreFGFR inhibitor resistance mutations has an increased likelihood ofhaving a positive response to treatment with a first FGFR inhibitor as amonotherapy as compared to a subject having a cancer cell that has oneor more FGFR inhibitor resistance mutations. Also provided are methodsof predicting the efficacy of treatment with a first FGFR inhibitor as amonotherapy in a subject having cancer that include: determining whethera cancer cell in a sample obtained from the subject has one or more FGFRinhibitor resistance mutations; and determining that treatment with afirst FGFR inhibitor as a monotherapy is less likely to be effective ina subject having a cancer cell in a sample obtained from the subjectthat has one or more FGFR inhibitor resistance mutations. Also providedare methods of predicting the efficacy of treatment with a first FGFRinhibitor as a monotherapy in a subject having cancer that include:determining that treatment with a first FGFR inhibitor as a monotherapyis less likely to be effective in a subject having a cancer cell in asample obtained from the subject that has one or more FGFR inhibitorresistance mutations. In some embodiments, the one or more FGFRinhibitor resistance mutations confer increased resistance to a cancercell or tumor to treatment with the first FGFR inhibitor. In someembodiments, the one or more FGFR inhibitor resistance mutations includeone or more FGFR inhibitor resistance mutations listed in Table BE. Forexample, the one or more FGFR inhibitor resistance mutations can includea substitution at an amino acid position corresponding to amino acidposition 561 in SEQ ID NO. 1 (e.g., V561M), amino acid position 564 inSEQ ID NO. 3 (e.g., V564I or V564F), or amino acid position 555 in SEQID NO. 5 (e.g., V555M).

Also provided are methods of selecting a treatment for a subject havinga cancer that include (a) administering one or more doses of a firstFGFR inhibitor to the subject for a period of time; (b) after (a),determining whether a cancer cell in a sample obtained from the subjecthas at least one FGFR inhibitor resistance mutation; and (c) selecting acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof as a monotherapy or in conjunction with an additional therapy ortherapeutic agent for the subject if the subject has a cancer cell thathas one or more FGFR inhibitor resistance mutations; or (d) selectingadditional doses of the first FGFR inhibitor of step (a) for the subjectif the subject has a cancer cell that does not have a FGFR inhibitorresistance mutation. In some embodiments, when additional doses of thefirst FGFR inhibitor of step (a) are selected for the subject, themethod can further include selecting doses of an additional therapy ortherapeutic agent for the subject. In some embodiments, the one or moreFGFR inhibitor resistance mutations confer increased resistance to acancer cell or tumor to treatment with the first FGFR inhibitor. In someembodiments, the one or more FGFR inhibitor resistance mutations includeone or more FGFR inhibitor resistance mutations listed in Table BE. Forexample, the one or more FGFR inhibitor resistance mutations can includea substitution at an amino acid position corresponding to amino acidposition 561 in SEQ ID NO. 1 (e.g., V561M), amino acid position 564 inSEQ ID NO. 3 (e.g., V564I or V564F), or amino acid position 555 in SEQID NO. 5 (e.g., V555M). In some embodiments, the additional therapy ortherapeutic agent is any anticancer agent known in the art. For example,the additional therapy or therapeutic agent is another FGFR inhibitor(e.g., a second FGFR inhibitor). In some embodiments, the additionaltherapy or therapeutic agent is an immunotherapy. In some embodiments ofstep (c), another FGFR inhibitor can be the first FGFR inhibitoradministered in step (a).

Also provided are methods of selecting a treatment for a subject havinga cancer that include (a) administering one or more doses of a firstFGFR inhibitor to the subject for a period of time; (b) after (a),determining whether a cancer cell in a sample obtained from the subjecthas at least one FGFR inhibitor resistance mutation; and (c) selecting asecond FGFR inhibitor as a monotherapy or in conjunction with anadditional therapy or therapeutic agent if the subject has a cancer cellthat has one or more FGFR inhibitor resistance mutations; or (d)selecting additional doses of the first FGFR inhibitor of step (a) forthe subject if the subject has a cancer cell that does not have a FGFRinhibitor resistance mutation. In some embodiments, when additionaldoses of the first FGFR inhibitor of step (a) are selected for thesubject, the method can further include selecting doses of an additionaltherapy or therapeutic agent for the subject. In some embodiments, theone or more FGFR inhibitor resistance mutations confer increasedresistance to a cancer cell or tumor to treatment with the first FGFRinhibitor. In some embodiments, the one or more FGFR inhibitorresistance mutations include one or more FGFR inhibitor resistancemutations listed in Table BE. For example, the one or more FGFRinhibitor resistance mutations can include a substitution at an aminoacid position corresponding to amino acid position 561 in SEQ ID NO. 1(e.g., V561M), amino acid position 564 in SEQ ID NO. 3 (e.g., V564I orV564F), or amino acid position 555 in SEQ ID NO. 5 (e.g., V555M). Insome embodiments, the additional therapy or therapeutic agent is anyanticancer agent known in the art. For example, the additional therapyor therapeutic agent is another FGFR inhibitor (e.g., a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof). Insome embodiments, the additional therapy or therapeutic agent is animmunotherapy. In some embodiments, another FGFR inhibitor can be thefirst FGFR inhibitor administered in step (a).

Also provided are methods of selecting a treatment for a subject havinga cancer that include (a) determining whether a cancer cell in a sampleobtained from a subject having a cancer and previously administered oneor more doses of a first FGFR inhibitor has one or more FGFR inhibitorresistance mutations; (b) selecting a compound of Formula I or apharmaceutically acceptable salt or solvate thereof as a monotherapy orin conjunction with an additional therapy or therapeutic agent for thesubject if the subject has a cancer cell that has at least one FGFRinhibitor resistance mutation; or (c) selecting additional doses of thefirst FGFR inhibitor previously administered to the subject if thesubject has a cancer cell that does not have a FGFR inhibitor resistancemutation. In some embodiments, when additional doses of the first FGFRinhibitor previously administered to the subject are selected for thesubject, the method can further include selecting doses of an additionaltherapy or therapeutic agent (e.g., a compound of Formula I or apharmaceutically acceptable salt or solvate thereof or immunotherapy)for the subject. In some embodiments, the one or more FGFR inhibitorresistance mutations confer increased resistance to a cancer cell ortumor to treatment with the first FGFR inhibitor. In some embodiments,the one or more FGFR inhibitor resistance mutations include one or moreFGFR inhibitor resistance mutations listed in Table BE. For example, theone or more FGFR inhibitor resistance mutations can include asubstitution at an amino acid position corresponding to amino acidposition 561 in SEQ ID NO. 1 (e.g., V561M), amino acid position 564 inSEQ ID NO. 3 (e.g., V564I or V564F), or amino acid position 555 in SEQID NO. 5 (e.g., V555M). In some embodiments, the additional therapy ortherapeutic agent is any anticancer agent known in the art. For example,the additional therapy or therapeutic agent is another FGFR inhibitor(e.g., a second FGFR inhibitor). In some embodiments, the additionaltherapy or therapeutic agent is an immunotherapy. In some embodiments ofstep (c), another FGFR inhibitor can be the first FGFR inhibitoradministered in step (a).

Also provided are methods of selecting a treatment for a subject havinga cancer that include (a) determining whether a cancer cell in a sampleobtained from a subject having a cancer and previously administered oneor more doses of a first FGFR inhibitor has one or more FGFR inhibitorresistance mutations; (b) selecting a second FGFR inhibitor as amonotherapy or in conjunction with an additional therapy or therapeuticagent for the subject if the subject has a cancer cell that has at leastone FGFR inhibitor resistance mutation; or (c) selecting additionaldoses of the first FGFR inhibitor previously administered to the subjectif the subject has a cancer cell that does not have a FGFR inhibitorresistance mutation. In some embodiments, when additional doses of thefirst FGFR inhibitor previously administered to the subject are selectedfor the subject, the method can further include selecting doses of anadditional therapy or therapeutic agent (e.g., a compound of Formula Ior a pharmaceutically acceptable salt or solvate thereof, or animmunotherapy) for the subject. In some embodiments, the one or moreFGFR inhibitor resistance mutations confer increased resistance to acancer cell or tumor to treatment with the first FGFR inhibitor. In someembodiments, the one or more FGFR inhibitor resistance mutations includeone or more FGFR inhibitor resistance mutations listed in Table BE. Forexample, the one or more FGFR inhibitor resistance mutations can includea substitution at an amino acid position corresponding to amino acidposition 561 in SEQ ID NO. 1 (e.g., V561M), amino acid position 564 inSEQ ID NO. 3 (e.g., V564I or V564F), or amino acid position 555 in SEQID NO. 5 (e.g., V555M). In some embodiments, the additional therapy ortherapeutic agent is any anticancer agent known in the art. For example,the additional therapy or therapeutic agent is another FGFR inhibitor(e.g., a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof). In some embodiments, the additional therapy ortherapeutic agent is an immunotherapy. In some embodiments, another FGFRcan be the first FGFR inhibitor administered in step (a).

Also provided are methods of determining a subject's risk for developinga cancer that has some resistance to a first FGFR inhibitor thatinclude: determining whether a cell in a sample obtained from thesubject has one or more FGFR inhibitor resistance mutations; andidentifying a subject having a cell that has one or more FGFR inhibitorresistance mutations, as having an increased likelihood of developing acancer that has some resistance to the first FGFR inhibitor. Alsoprovided are methods of determining a subject's risk for developing acancer that has some resistance to a first FGFR inhibitor that include:identifying a subject having a cell that has one or more FGFR inhibitorresistance mutations, as having an increased likelihood of developing acancer that has some resistance to the first FGFR inhibitor. Alsoprovided are methods of determining the presence of a cancer that hassome resistance to a first FGFR inhibitor that include: determiningwhether a cancer cell in a sample obtained from the subject has one ormore FGFR inhibitor resistance mutations; and determining that thesubject having a cancer cell that has one or more FGFR inhibitorresistance mutations has a cancer that has some resistance to the firstFGFR inhibitor. Also provided are methods of determining the presence ofa cancer that has some resistance to a first FGFR inhibitor in a subjectthat include: determining that a subject having a cancer cell that hasone or more FGFR inhibitor resistance mutations, has a cancer that hassome resistance to the first FGFR inhibitor. In some embodiments, theone or more FGFR inhibitor resistance mutations confer increasedresistance to a cancer cell or tumor to treatment with the first FGFRinhibitor. In some embodiments, the one or more FGFR inhibitorresistance mutations include one or more FGFR inhibitor resistancemutations listed in Table BE. For example, the one or more FGFRinhibitor resistance mutations can include a substitution at an aminoacid position corresponding to amino acid position 561 in SEQ ID NO. 1(e.g., V561M), amino acid position 564 in SEQ ID NO. 3 (e.g., V564I orV564F), or amino acid position 555 in SEQ ID NO. 5 (e.g., V555M).

Also provided are methods of selecting a treatment for a subject havinga cancer that include: identifying a subject having a cancer cell thathas one or more FGFR inhibitor resistance mutations; and selecting atreatment that does not include a compound of Formula I or apharmaceutically acceptable salt or solvate thereof as a monotherapy forthe identified subject (e.g., a second FGFR kinase inhibitor). Alsoprovided are methods of selecting a treatment for a subject having acancer that include: selecting a treatment that does not include acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof as a monotherapy (e.g., a second FGFR kinase inhibitor) for asubject identified as having a cancer cell that has one or more FGFRinhibitor resistance mutations. Also provided are methods of selecting asubject having a cancer for a treatment that does not include a compoundof Formula I or a pharmaceutically acceptable salt or solvate thereof asa monotherapy (e.g., a second FGFR kinase inhibitor) that include:identifying a subject having a cancer cell that has one or more FGFRinhibitor resistance mutations; and selecting the identified subject fora treatment that does not include a compound of Formula I or apharmaceutically acceptable salt or solvate thereof as a monotherapy(e.g., a second FGFR kinase inhibitor). Also provided are methods ofselecting a subject having a cancer for a treatment that does notinclude a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof as a monotherapy (e.g., a second FGFR kinase inhibitor)that include: selecting a subject identified as having a cancer cellthat has one or more FGFR inhibitor resistance mutations for a treatmentthat does not include a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof as a monotherapy. In someembodiments, the one or more FGFR inhibitor resistance mutations conferincreased resistance to a cancer cell or tumor to treatment with acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof. In some embodiments, the one or more FGFR inhibitor resistancemutations include one or more FGFR inhibitor resistance mutations listedin Table BE. In some embodiments, the one or more FGFR inhibitorresistance mutations include one or more FGFR inhibitor resistancemutations in a cysteine. In some embodiments, the one or more FGFRinhibitor resistance mutations include a mutation in a cysteine thatcorresponds to Cys582 of SEQ ID NO: 5. In some embodiments, the one ormore FGFR inhibitor resistance mutations include a mutation in acysteine that corresponds to Cys790 of SEQ ID NO: 3.

Also provided are methods of determining the likelihood that a subjecthaving a cancer will have a positive response to treatment with acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof as a monotherapy that include: determining whether a cancer cellin a sample obtained from the subject has one or more FGFR inhibitorresistance mutations; and determining that the subject having the cancercell that has one or more FGFR inhibitor resistance mutations has adecreased likelihood of having a positive response to treatment with acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof as a monotherapy. Also provided are methods of determining thelikelihood that a subject having cancer will have a positive response totreatment with a compound of Formula I or a pharmaceutically acceptablesalt or solvate thereof as a monotherapy that include: determining thata subject having a cancer cell that has one or more FGFR inhibitorresistance mutations has a decreased likelihood of having a positiveresponse to treatment with a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof as a monotherapy. Also provided aremethods of predicting the efficacy of treatment with a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof as amonotherapy in a subject having cancer that include: determining whethera cancer cell in a sample obtained from the subject has one or more FGFRinhibitor resistance mutations; and determining that treatment with acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof as a monotherapy is less likely to be effective in a subjecthaving a cancer cell in a sample obtained from the subject that has oneor more FGFR inhibitor resistance mutations. Also provided are methodsof predicting the efficacy of treatment with a compound of Formula I ora pharmaceutically acceptable salt or solvate thereof as a monotherapyin a subject having cancer that include: determining that treatment witha compound of Formula I or a pharmaceutically acceptable salt or solvatethereof as a monotherapy is less likely to be effective in a subjecthaving a cancer cell in a sample obtained from the subject that has oneor more FGFR inhibitor resistance mutations. In some embodiments, theone or more FGFR inhibitor resistance mutations confer increasedresistance to a cancer cell or tumor to treatment with a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof.

Also provided are methods of selecting a treatment for a subject havinga cancer that include: (a) administering one or more doses of a compoundof Formula I or a pharmaceutically acceptable salt or solvate thereof tothe subject for a period of time; (b) after (a), determining whether acancer cell in a sample obtained from the subject has one or more FGFRinhibitor resistance mutations; and (c) selecting a second FGFRinhibitor or a second compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof as a monotherapy or in conjunctionwith an additional therapy or therapeutic agent for the subject if thesubject has a cancer cell that has a FGFR inhibitor resistance mutation;or (d) selecting additional doses of the compound of Formula I or apharmaceutically acceptable salt or solvate thereof of step (a) for thesubject if the subject has a cancer cell that does not have a FGFRinhibitor resistance mutation. In some embodiments, where additionaldoses of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof of step (a) are selected for the subject, the methodcan also include further selecting an additional therapy or therapeuticagent. In some embodiments, the one or more FGFR inhibitor resistancemutations confer increased resistance to a cancer cell or tumor totreatment with a compound of Formula I or a pharmaceutically acceptablesalt or solvate thereof. In some embodiments, the additional therapy ortherapeutic agent is any anticancer agent known in the art. For example,the additional therapy or therapeutic agent is another FGFR inhibitor(e.g., a second FGFR inhibitor). In some embodiments, the additionaltherapy or therapeutic agent is an immunotherapy. In some embodiments,another FGFR inhibitor can be the compound of Formula I or apharmaceutically acceptable salt or solvate thereof administered in step(a).

Also provided are methods of selecting a treatment for a subject havinga cancer that include: (a) determining whether a cancer cell in a sampleobtained from a subject having a cancer and previously administered oneor more doses of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof, has one or more FGFR inhibitorresistance mutations; (b) selecting a second FGFR inhibitor or a secondcompound of Formula I or a pharmaceutically acceptable salt or solvatethereof as a monotherapy or in conjunction with an additional therapy ortherapeutic agent for the subject if the subject has a cancer cell thathas a FGFR inhibitor resistance mutation; or (c) selecting additionaldoses of the compound of Formula I or a pharmaceutically acceptable saltor solvate thereof previously administered to the subject if the subjecthas a cancer cell that does not have a FGFR inhibitor resistancemutation. In some embodiments, where additional doses of the compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof ofstep (a) are selected for the subject, the method can also includefurther selecting an additional therapy or therapeutic agent. In someembodiments, the one or more FGFR inhibitor resistance mutations conferincreased resistance to a cancer cell or tumor to treatment with acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof. In some embodiments, the additional therapy or therapeuticagent is any anticancer agent known in the art. For example, theadditional therapy or therapeutic agent is another FGFR inhibitor (e.g.,a second FGFR inhibitor). In some embodiments, the additional therapy ortherapeutic agent is an immunotherapy. In some embodiments, another FGFRinhibitor can be the compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof administered in step (a).

Also provided are methods of determining a subject's risk for developinga cancer that has some resistance to a compound of Formula I or apharmaceutically acceptable salt or solvate thereof that include:determining whether a cell in a sample obtained from the subject has oneor more FGFR inhibitor resistance mutations; and identifying the subjectif the subject has a cell that has one or more FGFR inhibitor resistancemutations as having an increased likelihood of developing a cancer thathas some resistance to a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof. Also provided are methods ofdetermining a subject's risk for developing a cancer that has someresistance to a compound of Formula I or a pharmaceutically acceptablesalt or solvate thereof that include: identifying a subject having acell that has one or more FGFR inhibitor resistance mutations as havingan increased likelihood of developing a cancer that has some resistanceto a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof. Also provided are methods of determining the presenceof a cancer that has some resistance to a compound of Formula I or apharmaceutically acceptable salt or solvate thereof that includes:determining whether a cancer cell in a sample obtained from the subjecthas one or more FGFR inhibitor resistance mutations; and determiningthat the subject having the cancer cell that has one or more FGFRinhibitor resistance mutations has a cancer that has some resistance toa compound of Formula I or a pharmaceutically acceptable salt or solvatethereof. Also provided are methods of determining the presence of acancer that has some resistance to a compound of Formula I or apharmaceutically acceptable salt or solvate thereof in a subject thatinclude: determining that a subject having a cancer cell that has one ormore FGFR inhibitor resistance mutations has a cancer that has someresistance to a compound of Formula I or a pharmaceutically acceptablesalt or solvate thereof. In some embodiments, the one or more FGFRinhibitor resistance mutations confer increased resistance to a cancercell or tumor to treatment with a compound of Formula I or apharmaceutically acceptable salt or solvate thereof.

In some embodiments of any of the methods described herein, a FGFRinhibitor resistance mutation that confers increased resistance to acancer cell or tumor to treatment with a compound of Formula I or apharmaceutically acceptable salt or solvate thereof, can be any of theFGFR inhibitor resistance mutations listed in Table BE. In someembodiments of any of the methods described herein, a FGFR inhibitorresistance mutation that confers increased resistance to a cancer cellor tumor to treatment with a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof, can be a FGFR inhibitor resistancemutations in a cysteine. In some embodiments, a FGFR inhibitorresistance mutation can be a mutation in a cysteine that corresponds toCys582 of SEQ ID NO: 5. In some embodiments, a FGFR inhibitor resistancemutation can be a mutation in a cysteine that corresponds to Cys790 ofSEQ ID NO: 3.

In some embodiments, dysregulation of a second protein can be present ina subject. In some embodiments, a second protein can be dysregulatedbefore a FGFR protein is dysregulated. In some embodiments, a secondprotein can be dysregulated after a FGFR protein is dysregulated.Provided herein are methods useful when a second protein isdysregulated.

In some embodiments, a second protein can be MET. For example, a methodcan include: (a) detecting a dysregulation of a FGFR gene, a FGFRkinase, or the expression or activity or level of any of the same in asample from the subject; and (b) administering to the subject atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt thereof. In some embodiments, themethods further comprises (after (b)) (c) determining whether a cancercell in a sample obtained from the subject has at least one FGFRinhibitor resistance mutation (e.g., a MET dysregulation such as a METgene amplification); and (d) administering a second therapeutic agent,wherein the second therapeutic agent is crizotinib, as a monotherapy orin conjunction with a compound of Formula I or pharmaceuticallyacceptable salt thereof to the subject if the subject has a cancer cellthat has at least one FGFR inhibitor resistance mutation; or (e)administering additional doses of the compound of Formula I orpharmaceutically acceptable salt thereof of step (b) to the subject ifthe subject has a cancer cell that does not have a FGFR inhibitorresistance mutation. In some such embodiments, the method comprises (a)detecting one or more fusion proteins of Table BA and/or one or moreFGFR kinase protein point mutations/insertions of Table BC in a samplefrom the subject; and (b) administering to the subject a therapeuticallyeffective amount of a compound of Formula I or pharmaceuticallyacceptable salt thereof. In further embodiments, the methods furthercomprise (after (b)) (c) determining whether a cancer cell in a sampleobtained from the subject has at least one FGFR inhibitor resistancemutation (e.g., a MET dysregulation such as a MET gene amplification);and (d) administering a second therapeutic agent, wherein the secondtherapeutic agent is crizotinib, as a monotherapy or in conjunction witha compound of Formula I or pharmaceutically acceptable salt thereof tothe subject if the subject has a cancer cell that has at least one FGFRinhibitor resistance mutation; or (e) administering additional doses ofthe compound of Formula I or pharmaceutically acceptable salt thereof ofstep (b) to the subject if the subject has a cancer cell that does nothave a FGFR inhibitor resistance mutation.

In some embodiments, a second protein can be EGFR. In some embodiments,a cancer is an EGFR-associated cancer. For example, the method caninclude: (a) detecting a dysregulation of an EGFR gene, an EGFR kinase,or the expression or activity or level of any of the same in a samplefrom the subject; and (b) administering to the subject a therapeuticallyeffective amount of an EGFR inhibitor (e.g., osimertinib). In someembodiments, the methods further comprises (after (b)) (c) determiningwhether a cancer cell in a sample obtained from the subject has at leastone dysregulation of a FGFR gene, a FGFR kinase, or the expression oractivity or level of any of the same (e.g., a FGFR gene fusion); and (d)administering a compound of Formula I or pharmaceutically acceptablesalt thereof, as a monotherapy or in conjunction with the EGFR inhibitor(e.g., osimertinib) to the subject if the subject has a cancer cell thathas at least one dysregulation of a FGFR gene, a FGFR kinase, or theexpression or activity or level of any of the same (e.g., a FGFR genefusion); or (e) administering additional doses of the EGFR inhibitor(e.g., osimertinib) of step (b) to the subject if the subject has acancer cell that does not have a dysregulation of a FGFR gene, a FGFRkinase, or the expression or activity or level of any of the same (e.g.,a FGFR gene fusion). In some such embodiments, the method comprises (a)detecting a dysregulation of an EGFR gene, an EGFR kinase, or theexpression or activity or level of any of the same in a sample from thesubject; and (b) administering to the subject a therapeuticallyeffective amount of osimertinib. In further embodiments, the methodsfurther comprise (after (b)) (c) determining whether a cancer cell in asample obtained from the subject has one or more fusion proteins ofTable BA and/or one or more FGFR kinase protein pointmutations/insertions of Table BC; and (d) administering a compound ofFormula I or pharmaceutically acceptable salt thereof, as a monotherapyor in conjunction with osimertinib to the subject if the subject has acancer cell that has one or more fusion proteins of Table BA and/or oneor more FGFR kinase protein point mutations/insertions of Table BC; or(e) administering additional doses of the osimertinib of step (b) to thesubject if the subject has a cancer cell that does not have one or morefusion proteins of Table BA and/or one or more FGFR kinase protein pointmutations/insertions of Table BC.

In some embodiments, a FGFR-associated cancer as described herein canoccur in a subject along with a dysregulation of another gene, anotherprotein, or the expression or activity or level of any of the same. Insome embodiments, a dysregulation of another gene, another protein, orthe expression or activity or level of any of the same can occur beforea dysregulation of a FGFR gene, FGFR protein, or the expression oractivity or level of any of the same. In some embodiments, adysregulation of another gene, another protein, or the expression oractivity or level of any of the same can occur after a dysregulation ofa FGFR gene, FGFR protein, or the expression or activity or level of anyof the same.

The term “EGFR-associated cancer” as used herein refers to cancersassociated with or having a dysregulation of an EGFR gene, an EGFRkinase, or expression or activity, or level of any of the same.

The phrase “dysregulation of an EGFR gene, an EGFR kinase, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., an EGFR gene translocation that results in theexpression of a fusion protein, a deletion in an EGFR gene that resultsin the expression of an EGFR protein that includes a deletion of atleast one amino acid as compared to the wild-type EGFR protein, or amutation in an EGFR gene that results in the expression of a EGFRprotein with one or more point mutations, or an alternative splicedversion of an EGFR mRNA that results in an EGFR protein that results inthe deletion of at least one amino acid in the EGFR protein as comparedto the wild-type EGFR protein), or an EGFR gene amplification thatresults in overexpression of an EGFR protein or an autocrine activityresulting from the overexpression of an EGFR gene a cell, that resultsin a pathogenic increase in the activity of a kinase domain of an EGFRprotein (e.g., a constitutively active kinase domain of an EGFR protein)in a cell. As another example, a dysregulation of an EGFR gene, an EGFRprotein, or expression or activity, or level of any of the same, can bea mutation in an EGFR gene that encodes an EGFR protein that isconstitutively active or has increased activity as compared to a proteinencoded by a EGFR gene that does not include the mutation. For example,a dysregulation of an EGFR gene, a EGFR protein, or expression oractivity, or level of any of the same, can be the result of a gene orchromosome translocation which results in the expression of a fusionprotein that contains a first portion of EGFR that includes a functionalkinase domain, and a second portion of a partner protein (i.e., that isnot EGFR). In some examples, dysregulation of an EGFR gene, an EGFRprotein, or expression or activity, can be a result of a genetranslocation of one EGFR gene with another non-EGFR gene.

The term “wildtype EGFR” or “wild-type EGFR” describes a nucleic acid(e.g., an EGFR gene or an EGFR mRNA) or protein (e.g., an EGFR protein)that is found in a subject that does not have an EGFR-associated cancer(and optionally also does not have an increased risk of developing anEGFR-associated cancer and/or is not suspected of having anEGFR-associated cancer), or is found in a cell or tissue from a subjectthat does not have an EGFR-associated cancer (and optionally also doesnot have an increased risk of developing an EGFR-associated cancerand/or is not suspected of having an EGFR-associated cancer).

For example, a FGFR-associated cancer that exhibits a FGFR fusion canoccur in a subject along with one or more of: a dysregulation of a METgene, a MET protein, or the expression or activity or level of any ofthe same; a dysregulation of a PIK3CA gene, a PIK3CA protein, or theexpression or activity or level of any of the same; a dysregulation of aKRAS gene, a KRAS protein, or the expression or activity or level of anyof the same; a dysregulation of a EGFR gene, a EGFR protein, or theexpression or activity or level of any of the same (e.g., anamplification of a EGFR gene); a dysregulation of a RET gene, a RETprotein, or the expression or activity or level of any of the same(e.g., a fusion of an RET gene or an RET protein); a dysregulation of aCDK4 gene, a CDK4 protein, or the expression or activity or level of anyof the same (e.g., an amplification of a CDK4 gene); a dysregulation ofa mTOR gene, a mTOR protein, or the expression or activity or level ofany of the same; a dysregulation of a CDKN2A gene, a CDKN2A protein, orthe expression or activity or level of any of the same (e.g., a deletionin a CDKN2A gene or a CDKN2A protein); a dysregulation of a CDKN2B gene,a CDKN2B protein, or the expression or activity or level of any of thesame (e.g., a deletion in a CDKN2B gene or a CDKN2B protein); adysregulation of a NF1 gene, a NF1 protein, or the expression oractivity or level of any of the same; a dysregulation of a MYC gene, aMYC protein, or the expression or activity or level of any of the same(e.g., an amplification in a MYC gene); a dysregulation of a MDM2 gene,a MDM2 protein, or the expression or activity or level of any of thesame (e.g., an amplification in a MDM2 gene); a dysregulation of a GNASgene, a GNAS protein, or the expression or activity or level of any ofthe same; a dysregulation of a BRCA2 gene, a BRCA2 protein, or theexpression or activity or level of any of the same.

For example, a FGFR-associated cancer that exhibits a FGFR fusion canoccur in a subject along with one or more of: a dysregulation of a ALKgene, a ALK protein, or the expression or activity or level of any ofthe same; a dysregulation of a AKT gene, a AKT protein, or theexpression or activity or level of any of the same; a dysregulation of aaurora gene, a aurora protein, or the expression or activity or level ofany of the same; a dysregulation of a AXL gene, a AXL protein, or theexpression or activity or level of any of the same; a dysregulation of aBRAF gene, a BRAF protein, or the expression or activity or level of anyof the same; a dysregulation of a CDK gene, a CDK protein, or theexpression or activity or level of any of the same; a dysregulation of aEGFR gene, a EGFR protein, or the expression or activity or level of anyof the same; a dysregulation of a EHMT2 gene, a EHMT2 protein, or theexpression or activity or level of any of the same; a dysregulation of aERK gene, a ERK protein, or the expression or activity or level of anyof the same; a dysregulation of a FGFR1 gene, a FGFR1 protein, or theexpression or activity or level of any of the same; a dysregulation of aFGFR2 gene, a FGFR2 protein, or the expression or activity or level ofany of the same; a dysregulation of a FGFR3 gene, a FGFR3 protein, orthe expression or activity or level of any of the same; a dysregulationof a FGFR4 gene, a FGFR4 protein, or the expression or activity or levelof any of the same; a dysregulation of a FLT3 gene, a FLT3 protein, orthe expression or activity or level of any of the same; a dysregulationof a HER2 (also called erbB-2) gene, a HER2 (also called erbB-2)protein, or the expression or activity or level of any of the same; adysregulation of a HER3 (also called erbB-3) gene, a HER3 (also callederbB-3) protein, or the expression or activity or level of any of thesame; a dysregulation of a HER4 (also called erbB-4) gene, a HER4 (alsocalled erbB-4) protein, or the expression or activity or level of any ofthe same; a dysregulation of a IGFR gene, a IGFR protein, or theexpression or activity or level of any of the same; a dysregulation of aJAK1 gene, a JAK1 protein, or the expression or activity or level of anyof the same; a dysregulation of a JAK2 gene, a JAK2 protein, or theexpression or activity or level of any of the same; a dysregulation of aJAK3 gene, a JAK3 protein, or the expression or activity or level of anyof the same; a dysregulation of a Kit gene, a Kit protein, or theexpression or activity or level of any of the same; a dysregulation of aMEK gene, a MEK protein, or the expression or activity or level of anyof the same; a dysregulation of a MET gene, a MET protein, or theexpression or activity or level of any of the same; a dysregulation of amTOR gene, a mTOR protein, or the expression or activity or level of anyof the same; a dysregulation of a PDGFRα gene, a PDGFRα protein, or theexpression or activity or level of any of the same; a dysregulation of aPDGFRβ gene, a PDGFRβ protein, or the expression or activity or level ofany of the same; a dysregulation of a PI3K gene, a PI3K protein, or theexpression or activity or level of any of the same; a dysregulation of aRAC1 gene, a RAC1 protein, or the expression or activity or level of anyof the same; a dysregulation of a RAF gene, a RAF protein, or theexpression or activity or level of any of the same; a dysregulation of aRAS gene, a RAS protein, or the expression or activity or level of anyof the same; a dysregulation of a RET gene, a RET protein, or theexpression or activity or level of any of the same; a dysregulation of aROS1 gene, a ROS1 protein, or the expression or activity or level of anyof the same; a dysregulation of a SOS1 gene, a SOS1 protein, or theexpression or activity or level of any of the same; a dysregulation of atrkA gene, a trkA protein, or the expression or activity or level of anyof the same; a dysregulation of a trkB gene, a trkB protein, or theexpression or activity or level of any of the same; a dysregulation of atrkC gene, a trkC protein, or the expression or activity or level of anyof the same; a dysregulation of a VEGFR-1 gene, a VEGFR-1 protein, orthe expression or activity or level of any of the same; a dysregulationof a VEGFR-2 gene, a VEGFR-2 protein, or the expression or activity orlevel of any of the same; or a dysregulation of a VEGFR-3 gene, aVEGFR-3 protein, or the expression or activity or level of any of thesame.

In some embodiments, a FGFR-associated cancer that exhibits a mutationof a FGFR gene and/or a FGFR protein can occur in a subject along withone or more of: a dysregulation of a PIK3CA gene, a PIK3CA protein, orthe expression or activity or level of any of the same; a dysregulationof a KRAS gene, a KRAS protein, or the expression or activity or levelof any of the same; a dysregulation of a EGFR gene, a EGFR protein, orthe expression or activity or level of any of the same; a dysregulationof a gene in the MAPK signaling pathway, a protein in the MAPK signalingpathway, or the expression or activity or level of any of the same; adysregulation of a MEK gene, a MEK protein, or the expression oractivity or level of any of the same; a dysregulation of a HER2 gene, aHER2 protein, or the expression or activity or level of any of the same(e.g., an amplification of HER2 gene); and a dysregulation of a KITgene, a KIT protein, or the expression or activity or level of any ofthe same.

In some embodiments, a FGFR-associated cancer that exhibits a mutationof a FGFR gene and/or a FGFR protein can occur in a subject along withone or more of: a dysregulation of a ALK gene, a ALK protein, or theexpression or activity or level of any of the same; a dysregulation of aAKT gene, a AKT protein, or the expression or activity or level of anyof the same; a dysregulation of a aurora gene, a aurora protein, or theexpression or activity or level of any of the same; a dysregulation of aAXL gene, a AXL protein, or the expression or activity or level of anyof the same; a dysregulation of a BRAF gene, a BRAF protein, or theexpression or activity or level of any of the same; a dysregulation of aCDK gene, a CDK protein, or the expression or activity or level of anyof the same; a dysregulation of a EGFR gene, a EGFR protein, or theexpression or activity or level of any of the same; a dysregulation of aEHMT2 gene, a EHMT2 protein, or the expression or activity or level ofany of the same; a dysregulation of a ERK gene, a ERK protein, or theexpression or activity or level of any of the same; a dysregulation of aFGFR1 gene, a FGFR1 protein, or the expression or activity or level ofany of the same; a dysregulation of a FGFR2 gene, a FGFR2 protein, orthe expression or activity or level of any of the same; a dysregulationof a FGFR3 gene, a FGFR3 protein, or the expression or activity or levelof any of the same; a dysregulation of a FGFR4 gene, a FGFR4 protein, orthe expression or activity or level of any of the same; a dysregulationof a FLT3 gene, a FLT3 protein, or the expression or activity or levelof any of the same; a dysregulation of a HER2 (also called erbB-2) gene,a HER2 (also called erbB-2) protein, or the expression or activity orlevel of any of the same; a dysregulation of a HER3 (also called erbB-3)gene, a HER3 (also called erbB-3) protein, or the expression or activityor level of any of the same; a dysregulation of a HER4 (also callederbB-4) gene, a HER4 (also called erbB-4) protein, or the expression oractivity or level of any of the same; a dysregulation of a IGFR gene, aIGFR protein, or the expression or activity or level of any of the same;a dysregulation of a JAK1 gene, a JAK1 protein, or the expression oractivity or level of any of the same; a dysregulation of a JAK2 gene, aJAK2 protein, or the expression or activity or level of any of the same;a dysregulation of a JAK3 gene, a JAK3 protein, or the expression oractivity or level of any of the same; a dysregulation of a Kit gene, aKit protein, or the expression or activity or level of any of the same;a dysregulation of a MEK gene, a MEK protein, or the expression oractivity or level of any of the same; a dysregulation of a MET gene, aMET protein, or the expression or activity or level of any of the same;a dysregulation of a mTOR gene, a mTOR protein, or the expression oractivity or level of any of the same; a dysregulation of a PDGFRα gene,a PDGFRα protein, or the expression or activity or level of any of thesame; a dysregulation of a PDGFRβ gene, a PDGFRβ protein, or theexpression or activity or level of any of the same; a dysregulation of aPI3K gene, a PI3K protein, or the expression or activity or level of anyof the same; a dysregulation of a RAC1 gene, a RAC1 protein, or theexpression or activity or level of any of the same; a dysregulation of aRAF gene, a RAF protein, or the expression or activity or level of anyof the same; a dysregulation of a RAS gene, a RAS protein, or theexpression or activity or level of any of the same; a dysregulation of aRET gene, a RET protein, or the expression or activity or level of anyof the same; a dysregulation of a ROS1 gene, a ROS1 protein, or theexpression or activity or level of any of the same; a dysregulation of aSOS1 gene, a SOS1 protein, or the expression or activity or level of anyof the same; a dysregulation of a trkA gene, a trkA protein, or theexpression or activity or level of any of the same; a dysregulation of atrkB gene, a trkB protein, or the expression or activity or level of anyof the same; a dysregulation of a trkC gene, a trkC protein, or theexpression or activity or level of any of the same; a dysregulation of aVEGFR-1 gene, a VEGFR-1 protein, or the expression or activity or levelof any of the same; a dysregulation of a VEGFR-2 gene, a VEGFR-2protein, or the expression or activity or level of any of the same; or adysregulation of a VEGFR-3 gene, a VEGFR-3 protein, or the expression oractivity or level of any of the same.

In some embodiments, a FGFR-associated cancer that exhibits anamplification of a FGFR gene can occur in a subject along with one ormore additional kinase amplifications. For example, an amplification ina gene in the MAPK signaling pathway; an amplification in a MEK gene; anamplification of a CDK4 gene; and an amplification in a CDK6 gene.

In some embodiments, wherein a FGFR-associated cancer as describedherein can occur in a subject along with a dysregulation in anotherkinase, the methods described herein can further comprise administrationof an additional therapeutic agent that targets and/or treats thedysregulation in the other kinase. For example, provided herein aremethods for treating a FGFR-associated cancer in a subject in need ofsuch treatment, the method comprising (a) detecting a dysregulation of aFGFR gene, a FGFR kinase, or the expression or activity or level of anyof the same in a sample from the subject; and (b) administering to thesubject a therapeutically effective amount of a compound of Formula I,or a pharmaceutically acceptable salt or solvate thereof. In someembodiments, the method further comprises (c) detecting a dysregulationin another kinase in a sample from the subject; and (d) administering tothe subject a therapeutic agent that targets and/or treats thedysregulation in the other kinase. In some embodiments, theadministration of a compound of Formula I, or a pharmaceuticallyacceptable salt or solvate thereof is done concurrently, sequentially,or serially. In some embodiments, the detecting steps (a) and (c) can bedone simultaneously or sequentially in any order.

Additional therapeutic agents that target and/or treat the dysregulationof an other kinase can include any known inhibitor of the other kinase.Examples of such agents are as follows:

Exemplary PARP inhibitors include: 3-aminobenzamide (INO-1001),5-aminoisoquinoline, ABT472, ABT767, AG140361, AG14032, ANG2864,ANG3186, AZD2281, AZD2461, BGP-15, BSI101, BSI401, CEP6800, CEP8983,CK102, CEP9722 (prodrug of CEP8983), CPH101 with CPH102, DR2313, E7016(GPI-21016), E7449, GP16150, IMP4297, IMP04149, IN01002, INO1003,JPI283, JPI289, KU0687, KU58948, niraparib (MK-4827), NT125, olaparib(AZD2281), ONO-1924H, ONO2231, pamiparib (BGB-290), PJ-34, rucaparib(AG014699), SC10914, SOMCL9112, talazoparib (BMN-673), and veliparib(ABT-888).

Exemplary CDK 4/6 inhibitors include: palbocidib (PD0332991),abemaciclib (LY2835219), ribociclib (LEE011), trilacidib (G1T28),vorucidib, and G1T38.

Exemplary ERBB2 (HER2/neu) inhibitors include: afatinib, afatinib,dacomitinib (PF-00299804), DS8201-a, erlontinib, gefitinib, KU004,lapatinib, laptinib ditosylate, MM-111, mubritinib (TAK-165), neratinib,pyrotinib (HTI-1001), tucatinib (ONT-380, ARRY-380), 7C3, cetuximab,HER2-BsAb, hersintuzumab, margetuximab, MI130004, NeuVax, paitumumab,pertuzumab, SYD985, trastuzumab, and trastuzumab emtansine.

Exemplary inhibitors of amplified ERBB2 (HER2/neu) include dacomitinib(PF-00299804), lapatinib, neratinib, pertuzumab, trastuzumab, andtrastuzumab emtansine.

Exemplary EGFR inhibitors include: AC0010, AEE788, afatinib, AP26113,ASP8273, avitinib, AZD3759, BIBX-1382(N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine),BMS-690514, brigatinib, canertinib, Cap-701, CHMFL-EGFR-202, CL-387785,CUDC-101, dacomitinib, EAI045, EGF816, erlontinib, eriotinib, gefitinib,GNS-1481, GNS-1486, Gö6976, HS-10296, icotinib, KU004, lapatinib,nazartinib, neratinib, olmutinib (HM61713, BI 1482694), osimertinib(AZD9291), pelitinib (EKB-569;(E)-N-[4-(3-chloro-4-fluoroanilino)-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide),PD 183805 (C11033,N-[4-(3-chloro-4-fluoroanilino)-7-(3-morpholin-4-ylpropoxy)quinazolin-6-yl]prop-2-enamide),PF-06747775, PKC412, PKI-166((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol);(R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine),poziotinib (HM781-36), pyrotinib (HTI-1001), rocilentinib, sapitinib,vandetanib, varlitinib, XL647, ZM 105180((6-amino-4-(3-methylphenyl-amino)-quinazoline), 7C3, ABX-EGF,cetuximab, depatuxizumab mafodotin (ABT-414), EMD55900, GA201 (RG7160),IMC-11F8, MAb 225 (ATCC CRL 8508), MAb 455 (ATCC CRL HB8507), MAb 528(ATCC CRL 8509), MAb 579 (ATCC CRL HB 8506), mAb806, mAb806 (humanized),matuzumab (EMD7200), MDX-447, nimotuzumab, panitumumab, Pertuzumab,reshaped human 225 (H225), and zalutumumab.

Exemplary wild-type EGFR inhibitors include: afatinib, BMS-690514,canertinib, CUDC-101, dacomitinib, eriotinib, gefitinib, lapatinib,neratinib, pelitinib, vandetanib, varlitinib, XL647, cetuximab,matuzumab, nimotuzumab, panitumumab, and zalutumumab.

Exemplary inhibitors of mutated EGFR include: AC0010, afatinib, AP26113,ASP8273, avatinib, avitinib, AZD3759, BMS-690514, brigatinib,canertinib, Cap-701, CHMFL-EGFR-202, CUDC-101, dacomitinib, EAI045,EGF816, GNS-1481, GNS-1486, Gö6976, HS-10296, icotinib, nazartinib,neratinib, olmutinib (HM61713, BI 1482694), osimertinib (AZD9291),PF-06747775, PKC412, rocilentinib, vandetanib, varlitinib, andcetuximab.

Additional exemplary EGFR inhibitors are described in U.S. Pat. Nos.4,943,533; 5,212,290; 5,457,105; 5,475,001; 5,616,582; 5,654,307;5,679,683; 5,747,498; 5,760,041; 5,770,599; 5,824,782; 5,866,572;5,891,996; 6,002,008; 6,084,095; 6,140,332; 6,235,883; 6,265,410;6,344,455; 6,344,459; 6,391,874; 6,399,602; 6,455,534; 6,521,620;6,596,726; 6,602,863; 6,713,484; and 6,727,256; and PCT Publication Nos.1996/040210; 1998/014451; 1998/050038; and 1999/009016, each of which isherein incorporated by reference.

An exemplary inhibitor of amplified EGFR is depatuxizumab mafodotin(ABT-414).

Exemplary inhibitors of FGFR include: ASP5878, AZD4547, BGJ398, BLU9931,brivanib, cediranib, danusertib, DEBIO 1347, derazantinib (ARQ-087),dovitinib (CHIR258), E-3810, E7090, ENMD-2076, erdafitinib(JNJ-42756493), FGF401, FIIN-1, FIIN-2, FIIN-3, FRIN-1, INCB054828,L16H50, lenvatinib, lucitanib, LY2874455, masitinib (AB1010),nintedanib, NP603, orantinib (SU6668), pazopanib, PBI05204, PD089828,PD161570, PD166866, PD173074, ponatinib, PRN1371, regorafenib,rogaratinib (BAY-1163877), S49076, SOMCL-085, SPP86, SSR128129E, SU4984,SU5402, sunitinib, TAS-120, Tyrophostin AG 1296, FP-1039, GAL-F2,GAL-FR21, GAL-FR22, GAL-FR23, GP369, hLD1.vb, HMPL-453, LD1, MFGR1877S,MK-2461, MM-161, PRO-001, and R3Mab.

Exemplary inhibitors of FGFR fusions include: BGJ398, DEBIO 1347,derazantinib (ARQ-087), E7090, erdafitinib (JNJ-42756293), lucitanib,and TAS-120.

Exemplary inhibitors of FGFR1, FGFR2, and FGFR3 include: AZD4547,BGJ398, DEBIO 1347, E7090, INCB054828, S49076, SOMCL-085, and TAS-120.

Exemplary inhibitors of FGFR4 include: BLU-554, BLU9931, NVP-FGF401, andhLD1.vb.

Exemplary inhibitors of amplified FGFR1 include: AZD4547, BGJ398, DEBIO1347, derazantinib (ARQ-087), erdafitinib (JNJ-42756293), INCB054828,and lucitanib.

Exemplary inhibitors of amplified FGFR2 include: AZD4547, DEBIO 1347,derazantinib (ARQ-087), lucitanib, regorafenib, and TAS-120.

An exemplary inhibitor of amplified FGFR3 is AZD4547.

Exemplary MEK inhibitors include: AZD8330 (ARRY-424704), AZD6244(ARRY-142866), BI-84732S, binimetinib, BIX02188, BIX02189, CH4987655,CH5126766, CI-1040, cobemetinib (GDC-0973), EBI-1051, G-573, G8935,GDC-0623, Myricetin, nobiletin, PD0325901, PD184161, PD318088, PD98059,PD334581, pimasertib (AS-703026), refametinib (RDEA119, BAY 869766),selumetinib (AZD6244), SL-327, TAK-733, trametinib, and U0126.

Exemplary KRAS inhibitors include: 0375-0604, a covalentquinazoline-based switch II pocket (SIIP) compound, ARS-1620, AZD4785,and LP1.

Exemplary PI3K inhibitors include: 3-methyladenine, A66, alpelisib(BYL719), AMG319, apitolisib (GDC-0980, RG7422), AS-252424, AS-604850,AS-605240, AZD6842, AZD8186, AZD8835, BGT226 (NVP-BGT226), buparlisib(BKM120), CAY10505, CH5132799, copanlisib (BAY 80-6946), CUDC-907,CZC24832, dactolisib (BEZ235, NVP-BEZ235), DS7423, duvelisib (IPI-145,INK1197), GDC-0032, GDC-0084, GDC-0326, gedatolisib (PF-05212384,PKI-5587), GNE-317, GS-9820, GSK1059615, GSK2292767, GSK2636771, HS-173,IC-87114, Idelalisib (CAL-101, GS-1101), IPI-145, IPI-3063, IPI-549,LY294002, LY3023414, nemiralisib (GSK2269557), omipalisib (GSK2126458,GSK458), PF-04691502, PF-4989216, PI-103, PI-3065, pictilisib(GDC-0941), PIK-293, PIK-294, PIK-75, PIK-90, PIK-93, PIK-III,pilaralisib (XL147), PKI-587, PP-110, PQR309, PQR309, PW-12, PX-866,quercetin, S14161, SAR245409 (XL765), SAR260301, SAR405, serabelisib(INK-1117, MLN-1117, TAK-1117), SF-1126, SF-2523, SN32976, taselisib(GDC-0032), TB101110, TG100-115, TG100-713, TGR-1202, TGX-221,umbralisib (TGR-1202), voxtalisib (XL765, SAR245409), VPS34-IN1, VS-5584(SB2343), WJD008, wortmannin, and ZSTK474.

Exemplary KIT inhibitors include: AMG 706, amuvatinib (M P-470),APcK110, axitinib (AG-013736), AZD2932, dasatinib (BMS-354825),dovitinib (TKI-258, CHIR-258), EXEL-0862, imatinib, KI-328, masitinib(AB1010), midostaurin, MLN518, motesanib,N3-(6-aminopyridin-3-yl)-N1-(2-cyclopentylethyl)-4-methylisophthalamide,nilotinib, OSI-930, pazopanib (GW786034), pexidartinib (PLX3397),PKC412, PLX647, PP1, quizartinib (AC220), regorafenib (BAY 73-4506),semaxinib (SU 5416), sitravatinib (MGCD516), sorafenib, STI571, SU11248,SU9529, sunitinib, telatinib, tivozanib (AV-951), tyrphostin AG 1296,VX-322, and WBZ_4.

Exemplary MDM2 inhibitors include: (−)-parthenolide, ALRN6924, AM-8553,AMG232, CGM-097, DS-3032b, GEM240, HDM201, HLI98, idasanutlin (RG-7338),JapA, MI-219, MI-219, MI-319, MI-77301 (SAR405838), MK4828, MK-8242,MX69, NSC 207895 (XI-006), Nutlin-3, Nutlin-3a, Nutlin-3b, NVP-CFC218,NVP-CGM097, PXn727/822, RG7112, R02468, R05353, R05503781, serdemetan(JNJ-26854165), SP-141, and YH239-EE.

Exemplary inhibitors of amplified MDM2 include: AM-8553, AMG232,DS-3032b, MI-77301 (SAR405838), NSC 207895 (XI-006), Nutlin-3a,NVP-CFC218, NVP-CGM097, and RG7112.

Exemplary inhibitors of MET include: (−)-Oleocanthal, ABBV-399, AMG-208,AMG-337, AMG-458, amuvatinib (MP740,N-(1,3-benzodioxol-5-ylmethyl)-4-([1]benzofuro[3,2-d]pyrimidin-4-yl)piperazine-1-carbothioamide),ASLAN002, ASP-08001, ASP-08126, BAY-853474, BMS-754807, BMS-777607,BMS-794833, BMS-817378 (prodrug of BMS-794833), cabozantinib (XL184,BMS-907351), capmatinib(INCB28060,2-fluoro-N-methyl-4-{7-[(quinolin-6-yl)methyl]imidazo[1,2-b][1,2,4]triazin-2-yl}benzamide),crizotinib (PF-02341066), DE605, DP-3590, EMD-1204831, foretinib(GSK1363089, XL880), glesatinib (MGCD265), golvatinib (E7050),HM-5016504, INCB028060, JNJ-38877605, KRC-408, merestinib (LY2801653),MK-2461, MK8033, NPS-1034, NVP-BVU972, PF-04217903, PHA-665752, S49076,savolitinib (AZD6094, HMPL-504), SGX-523, SU11274, TAS-115, tivantinib(ARQ197,(3R,4R)-3-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-2,5-pyrrolidinedione),tepotinib (EMD1214063, MSC2156119J), volitinib,6-[di-fluoro(6-pyridin-4-yl[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl]quinoline,(E)-2-(1-(3-((7-fluoroquinolin-6-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)ethylidene)hydrazinecarboxamide,CE-355621, emibetuzumab, ficlatuzumab, LY2875358 (LA-480), onartuzumab,rilotuzumab, and Tak-701. Other exemplary MET inhibitors can be foundin, e.g., U.S. Pat. Nos. 10,085,982; 8,629,144; 8,497,368; and8,030,305, each of which is incorporated herein by reference.

Exemplary inhibitors of mTOR include: anthracimycin, apitolisib(GDC-0980, RG7422), AZD-8055, BGT226 (NVP-BGT226), CC-223, CZ415,dactolisib (BEZ235, NVP-BEZ235), DS7423, everolimus (RAD001), GDC-0084,GDC-0349, gedatolisib (PF-05212384, PKI-5587), GSK1059615, INK128,KU-0063794, LY3023414, MLN0128, omipalisib (GSK2126458, GSK458),OSI-027, OSU-53, Palomid 529 (P529), PF-04691502, PI-103, PKI-587,PP242, PQR309, ridafarolimus (AP-23573), sapanisertib (INK 128,MLN0128), SAR245409 (XL765), SF-1126, SF2523, sirolimus (rapamycin),SN32976, TAK228, temsirolimus (CCI-779, NSC 683864), Torin 1, Torin 2,torkinib (PP242), umirolimus, vistusertib (AZD2014), voxtalisib (XL765,SAR245409), VS-5584, VS-5584 (SB2343), WAY-600, WYE-125132 (WYE-132),WYE-354, WYE-687, XL388, and zotarolimus (ABT-578).

Exemplary inhibitors of MYC include: 10058-F4,10074-G5, and KSI-3716.

The phrase “dysregulation of a gene, a protein, or the expression oractivity or level of any of the same” refers to a genetic mutation(e.g., a chromosomal translocation that results in the expression of afusion protein including a kinase domain and a fusion partner, amutation in a gene that results in the expression of a protein thatincludes a deletion of at least one amino acid as compared to a wildtypeprotein, a mutation in a gene that results in the expression of aprotein with one or more point mutations as compared to a wildtypeprotein, a mutation in a gene that results in the expression of aprotein with at least one inserted amino acid as compared to a wildtypeprotein, a gene duplication that results in an increased level ofprotein in a cell, or a mutation in a regulatory sequence (e.g., apromoter and/or enhancer) that results in an increased level of proteinin a cell), an alternative spliced version of a mRNA that results in aprotein having a deletion of at least one amino acid in the protein ascompared to the wild-type protein), or increased expression (e.g.,increased levels) of a wildtype protein in a mammalian cell due toaberrant cell signaling and/or dysregulated autocrine/paracrinesignaling (e.g., as compared to a control non-cancerous cell). Asanother example, a dysregulation of a gene, a protein, or expression oractivity, or level of any of the same, can be a mutation in a gene thatencodes a protein that is constitutively active or has increasedactivity as compared to a protein encoded by a gene that does notinclude the mutation. For example, a dysregulation of a gene, a protein,or expression or activity, or level of any of the same, can be theresult of a gene or chromosome translocation which results in theexpression of a fusion protein that contains a first portion of aprotein that includes a functional kinase domain, and a second portionof a partner protein (i.e., that is not the primary protein). In someexamples, dysregulation of a gene, a protein, or expression or activityor level of any of the same can be a result of a gene translocation ofone gene with a different gene.

Treatment of a subject having a cancer with a multi-kinase inhibitor(MKI) or target-specific kinase inhibitor (e.g., an ALK inhibitor, anAKT inhibitor, an aurora inhibitor, an AXL inhibitor, a BRAF inhibitor,an EGFR inhibitor, an ERK inhibitor, a FGFR1 inhibitor, a FGFR2inhibitor, a FGFR3 inhibitor, a FGFR4 inhibitor, a FLT3 inhibitor, aHER2 (also called erbB-2) inhibitor, a HER3 (also called erbB-3)inhibitor, a HER4 (also called erbB-4) inhibitor, an IGFR inhibitor, aJAK1 inhibitor, a JAK2 inhibitor, a JAK 3 inhibitor, a Kit inhibitor, aMEK inhibitor, a MET inhibitor, a mTOR inhibitor, a PDGFRα inhibitor, aPDGFRβ inhibitor, a PI3K inhibitor, a RAF inhibitor, a RAS inhibitor, aRET inhibitor, a ROS inhibitor, a ROS1 inhibitor, a trkA inhibitor, atrkB inhibitor, a trkC inhibitor, a VEGFR-1 inhibitor, a VEGFR-2inhibitor, or a VEGFR-3 inhibitor) can result in dysregulation of a FGFRgene, a FGFR kinase, or the expression or activity or level of the samein the cancer, and/or resistance to a FGFR inhibitor. Such dysregulationis sometimes called bypass resistance, as, without being bound bytheory, it is believed that the dysregulation of a second protein (e.g.,a FGFR) causes resistance to a MKI or a target-specific inhibitor. See,e.g., Yang et al., J Biol Chem., 287(33):28087-98,2012; and Huang etal., Acta Pharm Sin B., 5(5):390-401, 2015.

Treatment of a subject having a FGFR-associated cancer with a FGFRinhibitor (e.g., a compound of Formula I) can result in dysregulation ofa second kinase gene, a second kinase, or the expression or activity orlevel of the same in the cancer, and/or resistance to the FGFRinhibitor. Such dysregulation is sometimes called bypass resistance, as,without being bound by theory, it is believed that the dysregulation ofa second kinase (e.g., ALK, AKT, aurora, AXL, BRAF, CDK, EGFR, ERK,FGFR1, FGFR2, FGFR3, FGFR4, FLT3, HER2 (also called erbB-2), HER3 (alsocalled erbB-3), HER4 (also called erbB-4), IGFR, JAK1, JAK2, JAK3, Kit,MEK, MET, mTOR, PDGFRα, PDGFRβ, PI3K, RAF, RAS, RET, ROS1, trkA, trkB,trkC, VEGFR-1, VEGFR-2, or VEGFR-3) causes resistance to a FGFRinhibitor (e.g., a compound of Formula I). See, e.g., Wang et al.,Oncogene 34(17):2167-2177,2015; and Kim et al., Oncogenesis 5(5):e241,2016.

Treatment of a subject having a cancer with target-specific kinaseinhibitor (e.g., an aromatase inhibitor, a EHMT2 inhibitor, a RAC1inhibitor, or a SOS1 inhibitor) can result in dysregulation of a FGFRgene, a FGFR kinase, or the expression or activity or level of the samein the cancer, and/or resistance to a FGFR inhibitor. Such dysregulationis sometimes called bypass resistance, as, without being bound bytheory, it is believed that the dysregulation of a second protein (e.g.,a FGFR) causes resistance a target-specific inhibitor. See, e.g., Yanget al., J Biol Chem., 287(33):28087-98,2012; and Huang et al., ActaPharm Sin B., 5(5):390-401, 2015.

Treatment of a subject having a FGFR-associated cancer with a FGFRinhibitor (e.g., a compound of Formula I) can result in dysregulation ofa second gene, a second protein, or the expression or activity or levelof the same in the cancer, and/or resistance to the FGFR inhibitor. Suchdysregulation is sometimes called bypass resistance, as, without beingbound by theory, it is believed that the dysregulation of a secondprotein (e.g., aromatase, EHMT2, RAC1, or SOS1) causes resistance to aFGFR inhibitor (e.g., a compound of Formula I). See, e.g., Wang et al.,Oncogene 34(17):2167-2177,2015; and Kim et al., Oncogenesis 5(5):e241,2016.

Treatment of a subject having a cancer with a FGFR inhibitor incombination with a multi-kinase inhibitor or a target-specific kinaseinhibitor (e.g., an ALK inhibitor, an AKT inhibitor, an aurorainhibitor, an AXL inhibitor, a BRAF inhibitor, an EGFR inhibitor, an ERKinhibitor, a FGFR1 inhibitor, a FGFR2 inhibitor, a FGFR3 inhibitor, aFGFR4 inhibitor, a FLT3 inhibitor, a HER2 (also called erbB-2)inhibitor, a HER3 (also called erbB-3) inhibitor, a HER4 (also callederbB-4) inhibitor, an IGFR inhibitor, a JAK1 inhibitor, a JAK2inhibitor, a JAK 3 inhibitor, a Kit inhibitor, a MEK inhibitor, a METinhibitor, a mTOR inhibitor, a PDGFRα inhibitor, a PDGFRβ inhibitor, aPI3K inhibitor, a RAF inhibitor, a RAS inhibitor, a RET inhibitor, aROS1 inhibitor, a trkA inhibitor, a trkB inhibitor, a trkC inhibitor, aVEGFR-1 inhibitor, a VEGFR-2 inhibitor, or a VEGFR-3 inhibitor) can haveincreased therapeutic efficacy as compared to treatment of the samesubject or a similar subject with the FGFR inhibitor as a monotherapy,or the multi-kinase inhibitor or the target-specific kinase inhibitor asa monotherapy.

Treatment of a subject having a cancer with a FGFR inhibitor incombination with a target-specific inhibitor (e.g., an aromataseinhibitor, a EHMT2 inhibitor, a RAC1 inhibitor, or a SOS1 inhibitor) canhave increased therapeutic efficacy as compared to treatment of the samesubject or a similar subject with the FGFR inhibitor as a monotherapy,or the multi-kinase inhibitor or the target-specific kinase inhibitor asa monotherapy. Accordingly, in some embodiments, an additional therapyor therapeutic agent can include an aromatase inhibitor (e.g., anyaromatase inhibitor provided herein or known in the art), a EHMT2inhibitor (e.g., any EHMT2 inhibitor provided herein or known in theart), a RAC1 inhibitor (e.g., any RAC1 inhibitor provided herein orknown in the art), or a SOS1 inhibitor (e.g., any SOS1 inhibitorprovided herein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein that include: (a) detecting adysregulation of a FGFR gene, a FGFR kinase, or the expression oractivity or level of any of the same in a sample from the subject, (b)administering to the subject a therapeutically effective amount of afirst FGFR inhibitor, (c) determining whether a sample from a subjectexhibits a dysregulation of a second kinase gene, a second kinase, orthe expression or activity or level of any of the same in a sample fromthe subject; and (d) administering an inhibitor of the second kinase inconjunction with an additional therapy or therapeutic agent to thesubject if the sample from the subject exhibits a dysregulation of asecond kinase gene, a second kinase, or the expression or activity orlevel of any of the same; or (e) administering additional doses of thefirst FGFR inhibitor of step (b) to the subject if the sample from thesubject does not exhibit a dysregulation of a second kinase gene, asecond kinase, or the expression or activity or level of any of thesame. In some embodiments, a second kinase is selected from the groupconsisting of ALK, AKT, aurora, AXL, BRAF, CDK, EGFR, ERK, FGFR1, FGFR2,FGFR3, FGFR4, FLT3, HER2 (also called erbB-2), HER3 (also callederbB-3), HER4 (also called erbB-4), IGFR, JAK1, JAK2, JAK3, Kit, MEK,MET, mTOR, PDGFRα, PDGFRβ, PI3K, RAF, RAS, RET, ROS1, trkA, trkB, trkC,VEGFR-1, VEGFR-2, and VEGFR-3. In some embodiments, the inhibitor of thesecond kinase is selected from the group consisting of axitinib,cabozantinib, cetuximab, crizotinib, dasatinib, erlotinib, gefitinib,ibrutinib, imatinib, lapatinib, nilotinib, panitumumab, pazopanib,pertuzumab, regorafenib, ruxolitinib, sorafenib, sunitinib, trastuzumab,vandetanib, and vemurafenib. In some embodiments, the second kinase is atyrosine kinase. In some embodiments, the dysregulation of a FGFR gene,a FGFR kinase, or the expression or activity or level of any of the sameis a point mutation (e.g., any of the point mutations in Table BC). Insome embodiments, the dysregulation of a FGFR gene, a FGFR kinase, orthe expression or activity or level of any of the same is a fusion(e.g., any of the fusions in Table BA). In some embodiments, a firstFGFR inhibitor is selected from the group consisting of ARQ-087,ASP5878, AZD4547, B-701, BAY1179470, BAY1187982, BGJ398, brivanib, Debio1347, dovitinib, E7090, erdafitinib, FPA144, HMPL-453, INCB054828,lenvatinib, lucitanib, LY3076226, MAX-40279, nintedanib, orantinib,pemigatinib, ponatinib, PRN1371, rogaratinib, sulfatinib, and TAS-120.

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein that include: (a) detecting adysregulation of a FGFR gene, a FGFR kinase, or the expression oractivity or level of any of the same in a sample from the subject, (b)administering to the subject a therapeutically effective amount of acompound of Formula I, or a pharmaceutically acceptable salt or solvatethereof, (c) determining whether a sample from a subject exhibits adysregulation of a second kinase gene, a second kinase, or theexpression or activity or level of any of the same in a sample from thesubject; and (d) administering an inhibitor of the second kinase inconjunction with an additional therapy or therapeutic agent to thesubject if the sample from the subject exhibits a dysregulation of asecond kinase gene, a second kinase, or the expression or activity orlevel of any of the same; or (e) administering additional doses of thecompound of Formula I, or a pharmaceutically acceptable salt or solvatethereof of step (b) to the subject if the sample from the subject doesnot exhibit a dysregulation of a second kinase gene, a second kinase, orthe expression or activity or level of any of the same. In someembodiments, a second kinase is selected from the group consisting ofALK, AKT, aurora, AXL, BRAF, CDK, EGFR, ERK, FGFR1, FGFR2, FGFR3, FGFR4,FLT3, HER2 (also called erbB-2), HER3 (also called erbB-3), HER4 (alsocalled erbB-4), IGFR, JAK1, JAK2, JAK3, Kit, MEK, MET, mTOR, PDGFRα,PDGFRβ, PI3K, RAF, RAS, RET, ROS1, trkA, trkB, trkC, VEGFR-1, VEGFR-2,and VEGFR-3. In some embodiments, the inhibitor of the second kinase isselected from the group consisting of axitinib, cabozantinib, cetuximab,crizotinib, dasatinib, erlotinib, gefitinib, ibrutinib, imatinib,lapatinib, nilotinib, panitumumab, pazopanib, pertuzumab, regorafenib,ruxolitinib, sorafenib, sunitinib, trastuzumab, vandetanib, andvemurafenib. In some embodiments, the second kinase is a tyrosinekinase. In some embodiments, the dysregulation of a FGFR gene, a FGFRkinase, or the expression or activity or level of any of the same is apoint mutation (e.g., any of the point mutations in Table BC). In someembodiments, the dysregulation of a FGFR gene, a FGFR kinase, or theexpression or activity or level of any of the same is a fusion (e.g.,any of the fusions in Table BA). In some embodiments, a first FGFRinhibitor is selected from the group consisting of ARQ-087, ASP5878,AZD4547, B-701, BAY1179470, BAY1187982, BGJ398, brivanib, Debio 1347,dovitinib, E7090, erdafitinib, FPA144, HMPL-453, INCB054828, lenvatinib,lucitanib, LY3076226, MAX-40279, nintedanib, orantinib, pemigatinib,ponatinib, PRN1371, rogaratinib, sulfatinib, and TAS-120.

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein that include: (a) determiningwhether a sample from a subject previously administered one or moredoses of a first FGFR inhibitor exhibits a dysregulation of a secondkinase gene, a second kinase, or the expression or activity or level ofany of the same in a sample from the subject; and (b) administering aninhibitor of the second kinase in conjunction with an additional therapyor therapeutic agent to the subject if the sample from the subjectexhibits a dysregulation of a second kinase gene, a second kinase, orthe expression or activity or level of any of the same; or (c)administering additional doses of the first FGFR inhibitor of step (b)to the subject if the sample from the subject does not exhibit adysregulation of a second kinase gene, a second kinase, or theexpression or activity or level of any of the same. In some embodiments,a second kinase is selected from the group consisting of ALK, AKT,aurora, AXL, BRAF, CDK, EGFR, ERK, FGFR1, FGFR2, FGFR3, FGFR4, FLT3,HER2 (also called erbB-2), HER3 (also called erbB-3), HER4 (also callederbB-4), IGFR, JAK1, JAK2, JAK3, Kit, MEK, MET, mTOR, PDGFRα, PDGFRβ,PI3K, RAF, RAS, RET, ROS1, trkA, trkB, trkC, VEGFR-1, VEGFR-2, andVEGFR-3. In some embodiments, the inhibitor of the second kinase isselected from the group consisting of axitinib, cabozantinib, cetuximab,crizotinib, dasatinib, erlotinib, gefitinib, ibrutinib, imatinib,lapatinib, nilotinib, panitumumab, pazopanib, pertuzumab, regorafenib,ruxolitinib, sorafenib, sunitinib, trastuzumab, vandetanib, andvemurafenib. In some embodiments, the second kinase is a tyrosinekinase. In some embodiments, the dysregulation of a FGFR gene, a FGFRkinase, or the expression or activity or level of any of the same is apoint mutation (e.g., any of the point mutations in Table BC). In someembodiments, the dysregulation of a FGFR gene, a FGFR kinase, or theexpression or activity or level of any of the same is a fusion (e.g.,any of the fusions in Table BA). In some embodiments, a first FGFRinhibitor is selected from the group consisting of ARQ-087, ASP5878,AZD4547, B-701, BAY1179470, BAY1187982, BGJ398, brivanib, Debio 1347,dovitinib, E7090, erdafitinib, FPA144, HMPL-453, INCB054828, lenvatinib,lucitanib, LY3076226, MAX-40279, nintedanib, orantinib, pemigatinib,ponatinib, PRN1371, rogaratinib, sulfatinib, and TAS-120.

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: (a) determiningwhether a sample from a subject previously administered one or moredoses of a compound of Formula I, or a pharmaceutically acceptable saltor solvate thereof, exhibits a dysregulation of a second kinase gene, asecond kinase, or the expression or activity or level of any of the samein a sample from the subject; and (b) administering an inhibitor of thesecond kinase in conjunction with an additional therapy or therapeuticagent to the subject if the sample from the subject exhibits adysregulation of a second kinase gene, a second kinase, or theexpression or activity or level of any of the same; or (c) administeringadditional doses of the compound of Formula I, or a pharmaceuticallyacceptable salt or solvate thereof, of step (b) to the subject if thesample from the subject does not exhibit a dysregulation of a secondkinase gene, a second kinase, or the expression or activity or level ofany of the same. In some embodiments, a second kinase is selected fromthe group consisting of ALK, AKT, aurora, AXL, BRAF, CDK, EGFR, ERK,FGFR1, FGFR2, FGFR3, FGFR4, FLT3, HER2 (also called erbB-2), HER3 (alsocalled erbB-3), HER4 (also called erbB-4), IGFR, JAK1, JAK2, JAK3, Kit,MEK, MET, mTOR, PDGFRα, PDGFRβ, PI3K, RAF, RAS, RET, ROS1, trkA, trkB,trkC, VEGFR-1, VEGFR-2, and VEGFR-3. In some embodiments, the inhibitorof the second kinase is selected from the group consisting of axitinib,cabozantinib, cetuximab, crizotinib, dasatinib, erlotinib, gefitinib,ibrutinib, imatinib, lapatinib, nilotinib, panitumumab, pazopanib,pertuzumab, regorafenib, ruxolitinib, sorafenib, sunitinib, trastuzumab,vandetanib, and vemurafenib. In some embodiments, the second kinase is atyrosine kinase. In some embodiments, the dysregulation of a FGFR gene,a FGFR kinase, or the expression or activity or level of any of the sameis a point mutation (e.g., any of the point mutations in Table BC). Insome embodiments, the dysregulation of a FGFR gene, a FGFR kinase, orthe expression or activity or level of any of the same is a fusion(e.g., any of the fusions in Table BA).

Also provided herein are methods of treating a subject in need of suchtreatment, including: (a) detecting a dysregulation of a first kinasegene, a first kinase, or the expression or activity or level of any ofthe same in a sample from the subject, (b) administering to the subjecta therapeutically effective amount of an inhibitor of the first kinase,(c) determining whether a sample from a subject exhibits a dysregulationof a FGFR gene, a FGFR kinase, or the expression or activity or level ofany of the same, and (d) administering a FGFR inhibitor in conjunctionwith an additional therapy or therapeutic agent to the subject if thesample from the subject exhibits a dysregulation of a FGFR gene, a FGFRkinase, or the expression or activity or level of any of the same, or(e) administering additional doses of the inhibitor of the first kinaseof step (b) to the subject if the sample from the subject does notexhibit a dysregulation of a FGFR gene, a FGFR kinase, or the expressionor activity or level of any of the same. In some embodiments, a firstkinase is selected from the group consisting of ALK, AKT, aurora, AXL,BRAF, CDK, EGFR, ERK, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, HER2 (alsocalled erbB-2), HER3 (also called erbB-3), HER4 (also called erbB-4),IGFR, JAK1, JAK2, JAK3, Kit, MEK, MET, mTOR, PDGFRα, PDGFRβ, PI3K, RAF,RAS, RET, ROS1, trkA, trkB, trkC, VEGFR-1, VEGFR-2, and VEGFR-3. In someembodiments, the first kinase is a tyrosine kinase. In some embodiments,the inhibitor of the first kinase is selected from the group consistingof axitinib, cabozantinib, cetuximab, crizotinib, dasatinib, erlotinib,gefitinib, ibrutinib, imatinib, lapatinib, nilotinib, panitumumab,pazopanib, pertuzumab, regorafenib, ruxolitinib, sorafenib, sunitinib,trastuzumab, vandetanib, and vemurafenib. In some embodiments, thedysregulation of a FGFR gene, a FGFR kinase, or the expression oractivity or level of any of the same is a point mutation (e.g., any ofthe point mutations in Table BC). In some embodiments, the dysregulationof a FGFR gene, a FGFR kinase, or the expression or activity or level ofany of the same is a fusion (e.g., any of the fusions in Table BA). Insome embodiments, the FGFR inhibitor is a compound of Formula I or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the FGFR inhibitor is selected from the group consisting ofARQ-087, ASP5878, AZD4547, B-701, BAY1179470, BAY1187982, BGJ398,brivanib, Debio 1347, dovitinib, E7090, erdafitinib, FPA144, HMPL-453,INCB054828, lenvatinib, lucitanib, LY3076226, MAX-40279, nintedanib,orantinib, pemigatinib, ponatinib, PRN1371, rogaratinib, sulfatinib, andTAS-120.

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein that include: (a) detecting adysregulation of a FGFR gene, a FGFR kinase, or the expression oractivity or level of any of the same in a sample from the subject, (b)administering to the subject a therapeutically effective amount of afirst FGFR inhibitor, (c) determining whether a sample from a subjectexhibits a dysregulation of a second gene, a second protein, or theexpression or activity or level of any of the same in a sample from thesubject; and (d) administering an inhibitor of the second protein inconjunction with an additional therapy or therapeutic agent to thesubject if the sample from the subject exhibits a dysregulation of asecond kinase gene, a second kinase, or the expression or activity orlevel of any of the same; or (e) administering additional doses of thefirst FGFR inhibitor of step (b) to the subject if the sample from thesubject does not exhibit a dysregulation of a second gene, a secondprotein, or the expression or activity or level of any of the same. Insome embodiments, a second protein is selected from the group consistingof aromatase, EHMT2, RAC1, and SOS. In some embodiments, thedysregulation of a FGFR gene, a FGFR kinase, or the expression oractivity or level of any of the same is a point mutation (e.g., any ofthe point mutations in Table BC). In some embodiments, the dysregulationof a FGFR gene, a FGFR kinase, or the expression or activity or level ofany of the same is a fusion (e.g., any of the fusions in Table BA). Insome embodiments, a first FGFR inhibitor is selected from the groupconsisting of ARQ-087, ASP5878, AZD4547, B-701, BAY1179470, BAY1187982,BGJ398, brivanib, Debio 1347, dovitinib, E7090, erdafitinib, FPA144,HMPL-453, INCB054828, lenvatinib, lucitanib, LY3076226, MAX-40279,nintedanib, orantinib, pemigatinib, ponatinib, PRN1371, rogaratinib,sulfatinib, and TAS-120.

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein that include: (a) detecting adysregulation of a FGFR gene, a FGFR kinase, or the expression oractivity or level of any of the same in a sample from the subject, (b)administering to the subject a therapeutically effective amount of acompound of Formula I, or a pharmaceutically acceptable salt or solvatethereof, (c) determining whether a sample from a subject exhibits adysregulation of a second gene, a second protein, or the expression oractivity or level of any of the same in a sample from the subject; and(d) administering an inhibitor of the second protein in conjunction withan additional therapy or therapeutic agent to the subject if the samplefrom the subject exhibits a dysregulation of a second gene, a secondprotein, or the expression or activity or level of any of the same; or(e) administering additional doses of the compound of Formula I, or apharmaceutically acceptable salt or solvate thereof of step (b) to thesubject if the sample from the subject does not exhibit a dysregulationof a second gene, a second protein, or the expression or activity orlevel of any of the same. In some embodiments, a second protein isselected from the group consisting of aromatase, EHMT2, RAC1, and SOS1.In some embodiments, the dysregulation of a FGFR gene, a FGFR kinase, orthe expression or activity or level of any of the same is a pointmutation (e.g., any of the point mutations in Table BC). In someembodiments, the dysregulation of a FGFR gene, a FGFR kinase, or theexpression or activity or level of any of the same is a fusion (e.g.,any of the fusions in Table BA).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein that include: (a) determiningwhether a sample from a subject previously administered one or moredoses of a first FGFR inhibitor exhibits a dysregulation of a secondgene, a second protein, or the expression or activity or level of any ofthe same in a sample from the subject; and (b) administering aninhibitor of the second protein in conjunction with an additionaltherapy or therapeutic agent to the subject if the sample from thesubject exhibits a dysregulation of a second gene, a second protein, orthe expression or activity or level of any of the same; or (c)administering additional doses of the first FGFR inhibitor of step (b)to the subject if the sample from the subject does not exhibit adysregulation of a second gene, a second protein, or the expression oractivity or level of any of the same. In some embodiments, a secondprotein is selected from the group consisting of aromatase, EHMT2, RAC1,and SOS1. In some embodiments, the dysregulation of a FGFR gene, a FGFRkinase, or the expression or activity or level of any of the same is apoint mutation (e.g., any of the point mutations in Table BC). In someembodiments, the dysregulation of a FGFR gene, a FGFR kinase, or theexpression or activity or level of any of the same is a fusion (e.g.,any of the fusions in Table BA). In some embodiments, a first FGFRinhibitor is selected from the group consisting of ARQ-087, ASP5878,AZD4547, B-701, BAY1179470, BAY1187982, BGJ398, brivanib, Debio 1347,dovitinib, E7090, erdafitinib, FPA144, HMPL-453, INCB054828, lenvatinib,lucitanib, LY3076226, MAX-40279, nintedanib, orantinib, pemigatinib,ponatinib, PRN1371, rogaratinib, sulfatinib, and TAS-120.

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: (a) determiningwhether a sample from a subject previously administered one or moredoses of a compound of Formula I, or a pharmaceutically acceptable saltor solvate thereof, exhibits a dysregulation of a second gene, a secondprotein, or the expression or activity or level of any of the same in asample from the subject; and (b) administering an inhibitor of thesecond protein in conjunction with an additional therapy or therapeuticagent to the subject if the sample from the subject exhibits adysregulation of a second gene, a second protein, or the expression oractivity or level of any of the same; or (c) administering additionaldoses of the compound of Formula I, or a pharmaceutically acceptablesalt or solvate thereof, of step (b) to the subject if the sample fromthe subject does not exhibit a dysregulation of a second gene, a secondprotein, or the expression or activity or level of any of the same. Insome embodiments, a second protein is selected from the group consistingof aromatase, EHMT2, RAC1, and SOS1. In some embodiments, thedysregulation of a FGFR gene, a FGFR kinase, or the expression oractivity or level of any of the same is a point mutation (e.g., any ofthe point mutations in Table BC). In some embodiments, the dysregulationof a FGFR gene, a FGFR kinase, or the expression or activity or level ofany of the same is a fusion (e.g., any of the fusions in Table BA).

Also provided herein are methods of treating a subject in need of suchtreatment, including: (a) detecting a dysregulation of a first gene, afirst protein, or the expression or activity or level of any of the samein a sample from the subject, (b) administering to the subject atherapeutically effective amount of an inhibitor of the first protein,(c) determining whether a sample from a subject exhibits a dysregulationof a FGFR gene, a FGFR kinase, or the expression or activity or level ofany of the same, and (d) administering a FGFR inhibitor in conjunctionwith an additional therapy or therapeutic agent to the subject if thesample from the subject exhibits a dysregulation of a FGFR gene, a FGFRkinase, or the expression or activity or level of any of the same, or(e) administering additional doses of the inhibitor of the first proteinof step (b) to the subject if the sample from the subject does notexhibit a dysregulation of a FGFR gene, a FGFR kinase, or the expressionor activity or level of any of the same. In some embodiments, a firstprotein is selected from the group consisting of aromatase, EHMT2, RAC1,or SOS1. In some embodiments, the dysregulation of a FGFR gene, a FGFRkinase, or the expression or activity or level of any of the same is apoint mutation (e.g., any of the point mutations in Table BC). In someembodiments, the dysregulation of a FGFR gene, a FGFR kinase, or theexpression or activity or level of any of the same is a fusion (e.g.,any of the fusions in Table BA). In some embodiments, the FGFR inhibitoris a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments, the FGFR inhibitor is selectedfrom the group consisting of ARQ-087, ASP5878, AZD4547, B-701,BAY1179470, BAY1187982, BGJ398, brivanib, Debio 1347, dovitinib, E7090,erdafitinib, FPA144, HMPL-453, INCB054828, lenvatinib, lucitanib,LY3076226, MAX-40279, nintedanib, orantinib, pemigatinib, ponatinib,PRN1371, rogaratinib, sulfatinib, and TAS-120.

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) and previously administered amulti-kinase inhibitor (MKI) or a target-specific kinase inhibitor(e.g., an ALK inhibitor, an AXL inhibitor, a BRAF inhibitor, an EGFRinhibitor, an ERK inhibitor, a FGFR1 inhibitor, a FGFR2 inhibitor, aFGFR3 inhibitor, a FGFR4 inhibitor, a FLT3 inhibitor, a HER2 (alsocalled erbB-2) inhibitor, a HER3 (also called erbB-3) inhibitor, a HER4(also called erbB-4) inhibitor, an IGFR inhibitor, a JAK1 inhibitor, aJAK2 inhibitor, a JAK 3 inhibitor, a Kit inhibitor, a MEK inhibitor, aMET inhibitor, a mTOR inhibitor, a PDGFRα inhibitor, a PDGFRβ inhibitor,a PI3K inhibitor, a RAF inhibitor, a RAS inhibitor, a RET inhibitor, aROS1 inhibitor, a trkA inhibitor, a trkB inhibitor, a trkC inhibitor, aVEGFR-1 inhibitor, a VEGFR-2 inhibitor, or a VEGFR-3 inhibitor) (e.g.,as a monotherapy) that include: administering to the subject (i) atherapeutically effective dose of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof as a monotherapy, or(ii) a therapeutically effective dose of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof, and atherapeutically effective dose of the previously administered MKI or thepreviously administered target-specific kinase inhibitor.

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) previously administered a MKI or atarget specific kinase inhibitor (e.g., an ALK inhibitor, an AXLinhibitor, a BRAF inhibitor, an EGFR inhibitor, an ERK inhibitor, aFGFR1 inhibitor, a FGFR2 inhibitor, a FGFR3 inhibitor, a FGFR4inhibitor, a FLT3 inhibitor, a HER2 (also called erbB-2) inhibitor, aHER3 (also called erbB-3) inhibitor, a HER4 (also called erbB-4)inhibitor, an IGFR inhibitor, a JAK1 inhibitor, a JAK2 inhibitor, a JAK3 inhibitor, a Kit inhibitor, a MEK inhibitor, a MET inhibitor, a mTORinhibitor, a PDGFRα inhibitor, a PDGFRβ inhibitor, a PI3K inhibitor, aRAF inhibitor, a RAS inhibitor, a RET inhibitor, a ROS1 inhibitor, atrkA inhibitor, a trkB inhibitor, a trkC inhibitor, a VEGFR-1 inhibitor,a VEGFR-2 inhibitor, or a VEGFR-3 inhibitor) (e.g., as a monotherapy)that include: identifying a subject having a cancer cell that has adysregulation of a FGFR gene, a FGFR kinase, or the expression oractivity or level of the same; and administering to the identifiedsubject (i) a therapeutically effective dose of a compound of Formula Ior a pharmaceutically acceptable salt or solvate thereof as amonotherapy, or (ii) a therapeutically effective dose of a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof, anda therapeutically effective dose of the previously administered MKI orthe previously administered target-specific kinase inhibitor.

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: administering to asubject a therapeutically effective amount of a MKI or a target-specifickinase inhibitor (e.g., an ALK inhibitor, an AKT inhibitor, an aurorainhibitor, an AXL inhibitor, a BRAF inhibitor, an EGFR inhibitor, an ERKinhibitor, a FGFR1 inhibitor, a FGFR2 inhibitor, a FGFR3 inhibitor, aFGFR4 inhibitor, a FLT3 inhibitor, a HER2 (also called erbB-2)inhibitor, a HER3 (also called erbB-3) inhibitor, a HER4 (also callederbB-4) inhibitor, an IGFR inhibitor, a JAK1 inhibitor, a JAK2inhibitor, a JAK 3 inhibitor, a Kit inhibitor, a MEK inhibitor, a METinhibitor, a mTOR inhibitor, a PDGFRα inhibitor, a PDGFRβ inhibitor, aPI3K inhibitor, a RAF inhibitor, a RAS inhibitor, a RET inhibitor, aROS1 inhibitor, a trkA inhibitor, a trkB inhibitor, a trkC inhibitor, aVEGFR-1 inhibitor, a VEGFR-2 inhibitor, or a VEGFR-3 inhibitor) (e.g.,as a monotherapy) for a first period of time; after the period of time,identifying a subject having a cancer cell that has a dysregulation of aFGFR gene, a FGFR kinase, or the expression or activity or level of thesame; and administering to the identified subject (i) a therapeuticallyeffective dose of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof as a monotherapy, or (ii) atherapeutically effective dose of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof, and atherapeutically effective dose of the previously administered MKI or thepreviously administered target-specific kinase inhibitor.

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) and previously administeredtarget-specific inhibitor (e.g., an aromatase inhibitor, a EHMT2inhibitor, a RAC1 inhibitor, or a SOS1 inhibitor) (e.g., as amonotherapy) that include: administering to the subject (i) atherapeutically effective dose of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof as a monotherapy, or(ii) a therapeutically effective dose of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof, and atherapeutically effective dose of the previously administeredtarget-specific inhibitor.

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) previously a target specificinhibitor (e.g., an aromatase inhibitor, a EHMT2 inhibitor, a RAC1inhibitor, or a SOS1 inhibitor) (e.g., as a monotherapy) that include:identifying a subject having a cancer cell that has a dysregulation of aFGFR gene, a FGFR kinase, or the expression or activity or level of thesame; and administering to the identified subject (i) a therapeuticallyeffective dose of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof as a monotherapy, or (ii) atherapeutically effective dose of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof, and atherapeutically effective dose of the previously administeredtarget-specific inhibitor.

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: administering to asubject a therapeutically effective amount of a target-specificinhibitor (e.g., an aromatase inhibitor, a EHMT2 inhibitor, a RAC1inhibitor, or a SOS1 inhibitor) for a first period of time; after theperiod of time, identifying a subject having a cancer cell that has adysregulation of a FGFR gene, a FGFR kinase, or the expression oractivity or level of the same; and administering to the identifiedsubject (i) a therapeutically effective dose of a compound of Formula Ior a pharmaceutically acceptable salt or solvate thereof as amonotherapy, or (ii) a therapeutically effective dose of a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof, anda therapeutically effective dose of the previously administeredtarget-specific inhibitor.

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that has dysregulation of an ALKgene, an ALK protein, or the expression or activity or level of the samethat include administering to the subject (i) a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and (ii) a therapeutically effectiveamount of an ALK inhibitor (e.g., any of the ALK inhibitors describedherein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: identifying a subjecthaving a cancer cell that has dysregulation of an ALK gene, an ALKprotein, or the expression or activity or level of the same; andadministering to the identified subject (i) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and (ii) a therapeutically effective amount of an ALKinhibitor (e.g., any of the ALK inhibitors described herein or known inthe art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that has dysregulation of an AKTgene, an AKT protein, or the expression or activity or level of the samethat include administering to the subject (i) a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and (ii) a therapeutically effectiveamount of an AKT inhibitor (e.g., any of the AKT inhibitors describedherein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: identifying a subjecthaving a cancer cell that has dysregulation of an AKT gene, an AKTprotein, or the expression or activity or level of the same; andadministering to the identified subject (i) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and (ii) a therapeutically effective amount of an AKTinhibitor (e.g., any of the AKT inhibitors described herein or known inthe art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that has dysregulation of an auroragene, an aurora protein, or the expression or activity or level of thesame that include administering to the subject (i) a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and (ii) a therapeutically effectiveamount of an aurora inhibitor (e.g., any of the aurora inhibitorsdescribed herein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: identifying a subjecthaving a cancer cell that has dysregulation of an aurora gene, an auroraprotein, or the expression or activity or level of the same; andadministering to the identified subject (i) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and (ii) a therapeutically effective amount of anaurora inhibitor (e.g., any of the aurora inhibitors described herein orknown in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that has dysregulation of an AXLgene, an AXL protein, or the expression or activity or level of the samethat include administering to the subject (i) a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and (ii) a therapeutically effectiveamount of an AXL inhibitor (e.g., any of the AXL inhibitors describedherein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: identifying a subjecthaving a cancer cell that has dysregulation of an AXL gene, an AXLprotein, or the expression or activity or level of the same; andadministering to the identified subject (i) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and (ii) a therapeutically effective amount of an AXLinhibitor (e.g., any of the AXL inhibitors described herein or known inthe art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that has dysregulation of a BRAFgene, a BRAF kinase, or the expression or activity or level of the samethat include administering to the subject (i) a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and (ii) a therapeutically effectiveamount of a BRAF inhibitor (e.g., any of the BRAF inhibitors describedherein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: identifying a subjecthaving a cancer cell that has dysregulation of a BRAF gene, a BRAFkinase, or the expression or activity or level of the same; andadministering to the identified subject (i) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and (ii) a therapeutically effective amount of a BRAFinhibitor (e.g., any of the BRAF inhibitors described herein or known inthe art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that has dysregulation of an CDKgene, an CDK protein, or the expression or activity or level of the samethat include administering to the subject (i) a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and (ii) a therapeutically effectiveamount of an CDK inhibitor (e.g., any of the CDK inhibitors describedherein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: identifying a subjecthaving a cancer cell that has dysregulation of an CDK gene, an CDKprotein, or the expression or activity or level of the same; andadministering to the identified subject (i) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and (ii) a therapeutically effective amount of an CDKinhibitor (e.g., any of the CDK inhibitors described herein or known inthe art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that has dysregulation of an EGFRgene, an EGFR protein, or the expression or activity or level of thesame that include administering to the subject (i) a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and (ii) a therapeutically effectiveamount of an EGFR inhibitor (e.g., any of the EGFR inhibitors describedherein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: identifying a subjecthaving a cancer cell that has dysregulation of an EGFR gene, an EGFRprotein, or the expression or activity or level of the same; andadministering to the identified subject (i) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and (ii) a therapeutically effective amount of anEGFR inhibitor (e.g., any of the EGFR inhibitors described herein orknown in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that has dysregulation of an ERKgene, an ERK protein, or the expression or activity or level of the samethat include administering to the subject (i) a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and (ii) a therapeutically effectiveamount of an ERK inhibitor (e.g., any of the ERK inhibitors describedherein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: identifying a subjecthaving a cancer cell that has dysregulation of an ERK gene, an ERKprotein, or the expression or activity or level of the same; andadministering to the identified subject (i) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and (ii) a therapeutically effective amount of an ERKinhibitor (e.g., any of the ERK inhibitors described herein or known inthe art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that has dysregulation of an FLT3gene, an FLT3 protein, or the expression or activity or level of thesame that include administering to the subject (i) a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and (ii) a therapeutically effectiveamount of an FLT3 inhibitor (e.g., any of the FLT3 inhibitors describedherein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: identifying a subjecthaving a cancer cell that has dysregulation of an FLT3 gene, an FLT3protein, or the expression or activity or level of the same; andadministering to the identified subject (i) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and (ii) a therapeutically effective amount of anFLT3 inhibitor (e.g., any of the FLT3 inhibitors described herein orknown in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that has dysregulation of an HER2gene, an HER2 protein, or the expression or activity or level of thesame that include administering to the subject (i) a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and (ii) a therapeutically effectiveamount of an HER2 inhibitor (e.g., any of the HER2 inhibitors describedherein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: identifying a subjecthaving a cancer cell that has dysregulation of an HER2 gene, an HER2protein, or the expression or activity or level of the same; andadministering to the identified subject (i) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and (ii) a therapeutically effective amount of anHER2 inhibitor (e.g., any of the HER2 inhibitors described herein orknown in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that has dysregulation of an HER3gene, an HER3 protein, or the expression or activity or level of thesame that include administering to the subject (i) a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and (ii) a therapeutically effectiveamount of an HER3 inhibitor (e.g., any of the HER3 inhibitors describedherein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: identifying a subjecthaving a cancer cell that has dysregulation of an HER3 gene, an HER3protein, or the expression or activity or level of the same; andadministering to the identified subject (i) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and (ii) a therapeutically effective amount of anHER3 inhibitor (e.g., any of the HER3 inhibitors described herein orknown in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that has dysregulation of an IGFRgene, an IGFR protein, or the expression or activity or level of thesame that include administering to the subject (i) a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and (ii) a therapeutically effectiveamount of an IGFR inhibitor (e.g., any of the IGFR inhibitors describedherein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: identifying a subjecthaving a cancer cell that has dysregulation of an IGFR gene, an IGFRprotein, or the expression or activity or level of the same; andadministering to the identified subject (i) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and (ii) a therapeutically effective amount of anIGFR inhibitor (e.g., any of the IGFR inhibitors described herein orknown in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that has dysregulation of an JAK1gene, an JAK1 protein, or the expression or activity or level of thesame that include administering to the subject (i) a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and (ii) a therapeutically effectiveamount of an JAK1 inhibitor (e.g., any of the JAK1 inhibitors describedherein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: identifying a subjecthaving a cancer cell that has dysregulation of an JAK1 gene, an JAK1protein, or the expression or activity or level of the same; andadministering to the identified subject (i) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and (ii) a therapeutically effective amount of anJAK1 inhibitor (e.g., any of the JAK1 inhibitors described herein orknown in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that has dysregulation of an JAK2gene, an JAK2 protein, or the expression or activity or level of thesame that include administering to the subject (i) a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and (ii) a therapeutically effectiveamount of an JAK2 inhibitor (e.g., any of the JAK2 inhibitors describedherein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: identifying a subjecthaving a cancer cell that has dysregulation of an JAK2 gene, an JAK2protein, or the expression or activity or level of the same; andadministering to the identified subject (i) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and (ii) a therapeutically effective amount of anJAK2 inhibitor (e.g., any of the JAK2 inhibitors described herein orknown in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that has dysregulation of an JAK3gene, an JAK3 protein, or the expression or activity or level of thesame that include administering to the subject (i) a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and (ii) a therapeutically effectiveamount of an JAK3 inhibitor (e.g., any of the JAK3 inhibitors describedherein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: identifying a subjecthaving a cancer cell that has dysregulation of an JAK3 gene, an JAK3protein, or the expression or activity or level of the same; andadministering to the identified subject (i) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and (ii) a therapeutically effective amount of anJAK3 inhibitor (e.g., any of the JAK3 inhibitors described herein orknown in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that has dysregulation of a Kitgene, a Kit protein, or the expression or activity or level of the samethat include administering to the subject (i) a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and (ii) a therapeutically effectiveamount of a Kit inhibitor (e.g., any of the EGFR inhibitors describedherein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: identifying a subjecthaving a cancer cell that has dysregulation of a Kit gene, a Kitprotein, or the expression or activity or level of the same; andadministering to the identified subject (i) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and (ii) a therapeutically effective amount of a Kitinhibitor (e.g., any of the EGFR inhibitors described herein or known inthe art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that has dysregulation of a MEKgene, a MEK protein, or the expression or activity or level of the samethat include administering to the subject (i) a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and (ii) a therapeutically effectiveamount of a MEK inhibitor (e.g., any of the MEK inhibitors describedherein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: identifying a subjecthaving a cancer cell that has dysregulation of a MEK gene, a MEKprotein, or the expression or activity or level of the same; andadministering to the identified subject (i) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and (ii) a therapeutically effective amount of a MEKinhibitor (e.g., any of the MEK inhibitors described herein or known inthe art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that has dysregulation of a METgene, a MET protein, or the expression or activity or level of the samethat include administering to the subject (i) a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and (ii) a therapeutically effectiveamount of a MET inhibitor (e.g., any of the MET inhibitors describedherein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: identifying a subjecthaving a cancer cell that has dysregulation of a MET gene, a METprotein, or the expression or activity or level of the same; andadministering to the identified subject (i) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and (ii) a therapeutically effective amount of a METinhibitor (e.g., any of the MET inhibitors described herein or known inthe art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that has dysregulation of a mTORgene, a mTOR protein, or the expression or activity or level of the samethat include administering to the subject (i) a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and (ii) a therapeutically effectiveamount of a mTOR inhibitor (e.g., any of the mTOR inhibitors describedherein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: identifying a subjecthaving a cancer cell that has dysregulation of a mTOR gene, a mTORprotein, or the expression or activity or level of the same; andadministering to the identified subject (i) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and (ii) a therapeutically effective amount of a mTORinhibitor (e.g., any of the mTOR inhibitors described herein or known inthe art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that has dysregulation of a PDGFRαgene, a PDGFRα protein, or the expression or activity or level of thesame that include administering to the subject (i) a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and (ii) a therapeutically effectiveamount of a PDGFRα inhibitor (e.g., any of the PDGFRα inhibitorsdescribed herein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: identifying a subjecthaving a cancer cell that has dysregulation of a PDGFRα gene, a PDGFRαprotein, or the expression or activity or level of the same; andadministering to the identified subject (i) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and (ii) a therapeutically effective amount of aPDGFRα inhibitor (e.g., any of the PDGFRα inhibitors described herein orknown in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that has dysregulation of a PDGFRβgene, a PDGFRβ protein, or the expression or activity or level of thesame that include administering to the subject (i) a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and (ii) a therapeutically effectiveamount of a PDGFRβ inhibitor (e.g., any of the PDGFRβ inhibitorsdescribed herein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: identifying a subjecthaving a cancer cell that has dysregulation of a PDGFRβ gene, a PDGFRβprotein, or the expression or activity or level of the same; andadministering to the identified subject (i) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and (ii) a therapeutically effective amount of aPDGFRβ inhibitor (e.g., any of the PDGFRβ inhibitors described herein orknown in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that has dysregulation of a PI3Kgene, a PI3K protein, or the expression or activity or level of the samethat include administering to the subject (i) a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and (ii) a therapeutically effectiveamount of a PI3K inhibitor (e.g., any of the PI3K inhibitors describedherein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: identifying a subjecthaving a cancer cell that has dysregulation of a PI3K gene, a PI3Kprotein, or the expression or activity or level of the same; andadministering to the identified subject (i) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and (ii) a therapeutically effective amount of a PI3Kinhibitor (e.g., any of the PI3K inhibitors described herein or known inthe art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that has dysregulation of a RAFgene, a RAF protein, or the expression or activity or level of the samethat include administering to the subject (i) a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and (ii) a therapeutically effectiveamount of a RAF inhibitor (e.g., any of the RAF inhibitors describedherein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: identifying a subjecthaving a cancer cell that has dysregulation of a RAF gene, a RAFprotein, or the expression or activity or level of the same; andadministering to the identified subject (i) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and (ii) a therapeutically effective amount of a RAFinhibitor (e.g., any of the RAF inhibitors described herein or known inthe art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that has dysregulation of a RASgene, a RAS protein, or the expression or activity or level of the samethat include administering to the subject (i) a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and (ii) a therapeutically effectiveamount of a RAS inhibitor (e.g., any of the RAS inhibitors describedherein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: identifying a subjecthaving a cancer cell that has dysregulation of a RAS gene, a RASprotein, or the expression or activity or level of the same; andadministering to the identified subject (i) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and (ii) a therapeutically effective amount of a RASinhibitor (e.g., any of the RAS inhibitors described herein or known inthe art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that has dysregulation of a RETgene, a RET protein, or the expression or activity or level of the samethat include administering to the subject (i) a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and (ii) a therapeutically effectiveamount of a RET inhibitor (e.g., any of the RET inhibitors describedherein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: identifying a subjecthaving a cancer cell that has dysregulation of a RET gene, a RETprotein, or the expression or activity or level of the same; andadministering to the identified subject (i) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and (ii) a therapeutically effective amount of a RETinhibitor (e.g., any of the RET inhibitors described herein or known inthe art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that has dysregulation of a ROS1gene, a ROS1 protein, or the expression or activity or level of the samethat include administering to the subject (i) a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and (ii) a therapeutically effectiveamount of a ROS1 inhibitor (e.g., any of the ROS1 inhibitors describedherein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: identifying a subjecthaving a cancer cell that has dysregulation of a ROS1 gene, a ROS1protein, or the expression or activity or level of the same; andadministering to the identified subject (i) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and (ii) a therapeutically effective amount of a ROS1inhibitor (e.g., any of the ROS1 inhibitors described herein or known inthe art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that has dysregulation of a trkAgene, a trkA protein, or the expression or activity or level of the samethat include administering to the subject (i) a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and (ii) a therapeutically effectiveamount of a trkA inhibitor (e.g., any of the trkA inhibitors describedherein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: identifying a subjecthaving a cancer cell that has dysregulation of a trkA gene, a trkAprotein, or the expression or activity or level of the same; andadministering to the identified subject (i) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and (ii) a therapeutically effective amount of a trkAinhibitor (e.g., any of the trkA inhibitors described herein or known inthe art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that has dysregulation of a trkBgene, a trkB protein, or the expression or activity or level of the samethat include administering to the subject (i) a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and (ii) a therapeutically effectiveamount of a trkB inhibitor (e.g., any of the trkB inhibitors describedherein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: identifying a subjecthaving a cancer cell that has dysregulation of a trkB gene, a trkBprotein, or the expression or activity or level of the same; andadministering to the identified subject (i) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and (ii) a therapeutically effective amount of a trkBinhibitor (e.g., any of the trkB inhibitors described herein or known inthe art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that has dysregulation of a trkCgene, a trkC protein, or the expression or activity or level of the samethat include administering to the subject (i) a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and (ii) a therapeutically effectiveamount of a trkC inhibitor (e.g., any of the trkC inhibitors describedherein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: identifying a subjecthaving a cancer cell that has dysregulation of a trkC gene, a trkCprotein, or the expression or activity or level of the same; andadministering to the identified subject (i) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and (ii) a therapeutically effective amount of a trkCinhibitor (e.g., any of the trkC inhibitors described herein or known inthe art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that has dysregulation of a VEGFR-1gene, a VEGFR-1 protein, or the expression or activity or level of thesame that include administering to the subject (i) a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and (ii) a therapeutically effectiveamount of a VEGFR-1 inhibitor (e.g., any of the VEGFR-1 inhibitorsdescribed herein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: identifying a subjecthaving a cancer cell that has dysregulation of a VEGFR-1 gene, a VEGFR-1protein, or the expression or activity or level of the same; andadministering to the identified subject (i) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and (ii) a therapeutically effective amount of aVEGFR-1 inhibitor (e.g., any of the VEGFR-1 inhibitors described hereinor known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that has dysregulation of a VEGFR-2gene, a VEGFR-2 protein, or the expression or activity or level of thesame that include administering to the subject (i) a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and (ii) a therapeutically effectiveamount of a VEGFR-2 inhibitor (e.g., any of the VEGFR-2 inhibitorsdescribed herein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: identifying a subjecthaving a cancer cell that has dysregulation of a VEGFR-2 gene, a VEGFR-2protein, or the expression or activity or level of the same; andadministering to the identified subject (i) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and (ii) a therapeutically effective amount of aVEGFR-2 inhibitor (e.g., any of the VEGFR-2 inhibitors described hereinor known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that has dysregulation of a VEGFR-3gene, a VEGFR-3 protein, or the expression or activity or level of thesame that include administering to the subject (i) a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and (ii) a therapeutically effectiveamount of a VEGFR-3 inhibitor (e.g., any of the VEGFR-3 inhibitorsdescribed herein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: identifying a subjecthaving a cancer cell that has dysregulation of a VEGFR-3 gene, a VEGFR-3protein, or the expression or activity or level of the same; andadministering to the identified subject (i) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and (ii) a therapeutically effective amount of aVEGFR-3 inhibitor (e.g., any of the VEGFR-3 inhibitors described hereinor known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that has dysregulation of anaromatase gene, an aromatase protein, or the expression or activity orlevel of the same that include administering to the subject (i) atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof and (ii) atherapeutically effective amount of an aromatase inhibitor (e.g., any ofthe aromatase inhibitors described herein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: identifying a subjecthaving a cancer cell that has dysregulation of an aromatase gene, anaromatase protein, or the expression or activity or level of the same;and administering to the identified subject (i) a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and (ii) a therapeutically effectiveamount of an aromatase inhibitor (e.g., any of the aromatase inhibitorsdescribed herein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that has dysregulation of an EHMT2gene, an EHMT2 protein, or the expression or activity or level of thesame that include administering to the subject (i) a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and (ii) a therapeutically effectiveamount of an EHMT2 inhibitor (e.g., any of the EHMT2 inhibitorsdescribed herein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: identifying a subjecthaving a cancer cell that has dysregulation of an EHMT2 gene, an EHMT2protein, or the expression or activity or level of the same; andadministering to the identified subject (i) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and (ii) a therapeutically effective amount of anEHMT2 inhibitor (e.g., any of the EHMT2 inhibitors described herein orknown in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that has dysregulation of an RAC1gene, an RAC1 protein, or the expression or activity or level of thesame that include administering to the subject (i) a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and (ii) a therapeutically effectiveamount of an RAC1 inhibitor (e.g., any of the RAC1 inhibitors describedherein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: identifying a subjecthaving a cancer cell that has dysregulation of an RAC1 gene, an RAC1protein, or the expression or activity or level of the same; andadministering to the identified subject (i) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and (ii) a therapeutically effective amount of anRAC1 inhibitor (e.g., any of the RAC1 inhibitors described herein orknown in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that has dysregulation of an SOS1gene, an SOS1 protein, or the expression or activity or level of thesame that include administering to the subject (i) a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and (ii) a therapeutically effectiveamount of an SOS1 inhibitor (e.g., any of the SOS1 inhibitors describedherein or known in the art).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include: identifying a subjecthaving a cancer cell that has dysregulation of an SOS1 gene, an SOS1protein, or the expression or activity or level of the same; andadministering to the identified subject (i) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and (ii) a therapeutically effective amount of anSOS1 inhibitor (e.g., any of the SOS1 inhibitors described herein orknown in the art).

The phrase “dysregulation of a second kinase gene, a second kinaseprotein, or the expression or activity or level of any of the same”refers to a genetic mutation (e.g., a chromosomal translocation thatresults in the expression of a fusion protein including a second kinasedomain and a fusion partner, a mutation in a second kinase gene thatresults in the expression of a second kinase protein that includes adeletion of at least one amino acid as compared to a wildtype secondkinase protein, a mutation in a second kinase gene that results in theexpression of a second kinase protein with one or more point mutationsas compared to a wildtype second kinase protein, a mutation in a secondkinase gene that results in the expression of a second kinase proteinwith at least one inserted amino acid as compared to a wildtype secondkinase protein, a gene duplication that results in an increased level ofsecond kinase protein in a cell, or a mutation in a regulatory sequence(e.g., a promoter and/or enhancer) that results in an increased level ofsecond kinase protein in a cell), an alternative spliced version of asecond kinase mRNA that results in a second kinase protein having adeletion of at least one amino acid in the second kinase protein ascompared to the wild-type second kinase protein), or increasedexpression (e.g., increased levels) of a wildtype second kinase proteinin a mammalian cell due to aberrant cell signaling and/or dysregulatedautocrine/paracrine signaling (e.g., as compared to a controlnon-cancerous cell). As another example, a dysregulation of a secondkinase gene, a second kinase protein, or expression or activity, orlevel of any of the same, can be a mutation in a second kinase gene thatencodes a second kinase protein that is constitutively active or hasincreased activity as compared to a protein encoded by a second kinasegene that does not include the mutation. For example, a dysregulation ofa second kinase gene, a second kinase protein, or expression oractivity, or level of any of the same, can be the result of a gene orchromosome translocation which results in the expression of a fusionprotein that contains a first portion of a second kinase protein thatincludes a functional kinase domain, and a second portion of a partnerprotein (i.e., that is not second kinase). In some examples,dysregulation of a second kinase gene, a second kinase protein, orexpression or activity or level of any of the same can be a result of agene translocation of one second kinase gene with another non-secondkinase gene. When both a first and a second kinase are present in amethod provided herein, the first and second kinase are different. Insome embodiments, a second kinase is selected from the group consistingALK, AKT, aurora, AXL, BRAF, CDK, EGFR, ERK, FGFR1, FGFR2, FGFR3, FGFR4,FLT3, HER2 (also called erbB-2), HER3 (also called erbB-3), HER4 (alsocalled erbB-4), IGFR, JAK1, JAK2, JAK3, Kit, MEK, MET, mTOR, PDGFRα,PDGFRβ, PI3K, RAF, RAS, RET, ROS1, trkA, trkB, trkC, VEGFR-1, VEGFR-2,VEGFR-3.

The phrase “dysregulation of an ALK gene, an ALK protein, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a chromosomal translocation that results in theexpression of a fusion protein including an ALK kinase domain and afusion partner, a mutation in an ALK gene that results in the expressionan ALK protein that includes a deletion of at least one amino acid ascompared to a wildtype ALK protein, a mutation in an ALK gene thatresults in the expression of an ALK protein with one or more pointmutations as compared to a wildtype ALK protein, a mutation in an ALKgene that results in the expression of an ALK protein with at least oneinserted amino acid as compared to a wildtype ALK protein, a geneduplication that results in an increased level of ALK protein in a cell,or a mutation in a regulatory sequence (e.g., a promoter and/orenhancer) that results in an increased level of ALK protein in a cell),an alternative spliced version of an ALK mRNA that results in an ALKprotein having a deletion of at least one amino acid in the ALK proteinas compared to the wild-type ALK protein), or increased expression(e.g., increased levels) of a wildtype ALK protein in a mammalian celldue to aberrant cell signaling and/or dysregulated autocrine/paracrinesignaling (e.g., as compared to a control non-cancerous cell). Asanother example, a dysregulation of an ALK gene, an ALK protein, orexpression or activity, or level of any of the same, can be a mutationin an ALK gene that encodes an ALK protein that is constitutively activeor has increased activity as compared to a protein encoded by an ALKgene that does not include the mutation. For example, a dysregulation ofan ALK gene, an ALK protein, or expression or activity, or level of anyof the same, can be the result of a gene or chromosome translocationwhich results in the expression of a fusion protein that contains afirst portion of an ALK protein that includes a functional kinasedomain, and a second portion of a partner protein (i.e., that is notALK). In some examples, dysregulation of an ALK gene, an ALK protein, orexpression or activity or level of any of the same can be a result of agene translocation of one ALK gene with another non-ALK gene.

Non-limiting examples of an ALK inhibitor include crizotinib (Xalkori),ceritinib (Zykadia), alectinib (Alecensa), dalantercept, ACE-041(Brigatinib) (AP26113), entrectinib (NMS-E628), PF-06463922 (Pfizer),TSR-011 (Tesaro), CEP-37440 (Teva), CEP-37440 (Teva), X-396 (Xcovery),and ASP-3026 (Astellas). Additional examples of an ALK inhibitor areknown in the art.

The phrase “dysregulation of an AKT gene, an AKT protein, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a chromosomal translocation that results in theexpression of a fusion protein including an AKT kinase domain and afusion partner, a mutation in an AKT gene that results in the expressionan AKT protein that includes a deletion of at least one amino acid ascompared to a wild type AKT protein, a mutation in an AKT gene thatresults in the expression of an AKT protein with one or more pointmutations as compared to a wildtype AKT protein, a mutation in an AKTgene that results in the expression of an AKT protein with at least oneinserted amino acid as compared to a wildtype AKT protein, a geneduplication that results in an increased level of AKT protein in a cell,or a mutation in a regulatory sequence (e.g., a promoter and/orenhancer) that results in an increased level of AKT protein in a cell),an alternative spliced version of an AKT mRNA that results in an AKTprotein having a deletion of at least one amino acid in the AKT proteinas compared to the wild-type AKT protein), or increased expression(e.g., increased levels) of a wildtype AKT protein in a mammalian celldue to aberrant cell signaling and/or dysregulated autocrine/paracrinesignaling (e.g., as compared to a control non-cancerous cell). Asanother example, a dysregulation of an AKT gene, an AKT protein, orexpression or activity, or level of any of the same, can be a mutationin an AKT gene that encodes an AKT protein that is constitutively activeor has increased activity as compared to a protein encoded by an AKTgene that does not include the mutation. For example, a dysregulation ofan AKT gene, an AKT protein, or expression or activity, or level of anyof the same, can be the result of a gene or chromosome translocationwhich results in the expression of a fusion protein that contains afirst portion of an AKT protein that includes a functional kinasedomain, and a second portion of a partner protein (i.e., that is notAKT). In some examples, dysregulation of an AKT gene, an AKT protein, orexpression or activity or level of any of the same can be a result of agene translocation of one AKT gene with another non-AKT gene.

Non-limiting examples of an AKT inhibitor include2-[4-(2-aminoprop-2-yl)phenyl]-3-phenylquinoxaline; 3-oxo-tirucallicacid; A-443654; A-674563; afuresertib; API-1; ARQ092; AT13148; AT7867;AZD5363; BAY 1125976; boc-Phe-vinyl ketone; CCT128930; DC120; DM-PIT-1;edelfosine; erucylphophocholine; erufosine; GSK2141795; GSK690693; H-89;ipatasertib (GDC-0068, RG7440); lactoquinomycin; miltefosine(IMPADIVO®); MK-2206;N-(4-(5-(3-acetamidophenyl)-2-(2-aminopyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)-3-fluorobenzamide;NL-71-101; ONC201; OSU-A9; perifosine (D-21266); PH-316; PHT-427; PIT-1;SR13668; TCN; TCN-P; triciribine (Triciribine Phosphate Monohydrate);uprosertib; and wortmannin. Additional examples of an AKT inhibitor areknown in the art.

The phrase “dysregulation of an aurora gene, an aurora protein, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a chromosomal translocation that results in theexpression of a fusion protein including an aurora kinase domain and afusion partner, a mutation in an aurora gene that results in theexpression an aurora protein that includes a deletion of at least oneamino acid as compared to a wildtype aurora protein, a mutation in anaurora gene that results in the expression of an aurora protein with oneor more point mutations as compared to a wildtype aurora protein, amutation in an aurora gene that results in the expression of an auroraprotein with at least one inserted amino acid as compared to a wildtypeaurora protein, a gene duplication that results in an increased level ofaurora protein in a cell, or a mutation in a regulatory sequence (e.g.,a promoter and/or enhancer) that results in an increased level of auroraprotein in a cell), an alternative spliced version of an aurora mRNAthat results in an aurora protein having a deletion of at least oneamino acid in the aurora protein as compared to the wild-type auroraprotein), or increased expression (e.g., increased levels) of a wildtypeaurora protein in a mammalian cell due to aberrant cell signaling and/ordysregulated autocrine/paracrine signaling (e.g., as compared to acontrol non-cancerous cell). As another example, a dysregulation of anaurora gene, an aurora protein, or expression or activity, or level ofany of the same, can be a mutation in an aurora gene that encodes anaurora protein that is constitutively active or has increased activityas compared to a protein encoded by an aurora gene that does not includethe mutation. For example, a dysregulation of an aurora gene, an auroraprotein, or expression or activity, or level of any of the same, can bethe result of a gene or chromosome translocation which results in theexpression of a fusion protein that contains a first portion of anaurora protein that includes a functional kinase domain, and a secondportion of a partner protein (i.e., that is not aurora). In someexamples, dysregulation of an aurora gene, an aurora protein, orexpression or activity or level of any of the same can be a result of agene translocation of one aurora gene with another non-aurora gene.

Non-limiting examples of an aurora inhibitor include4-[[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-benzoicacid, CAS 869363-13-3); alisertib (MLN8237); AMG900; AT9283(N-cyclopropyl-N′-[3-[6-(4-morpholinylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl]-urea);barasertib (AZD1152); cenisertib (R-763); CYC116(4-(2-Amino-4-methyl-5-thiazolyl)-N-[4-(4-morpholinyl)phenyl]-2-pyrimidinamine,CAS 693228-63-6); danusertib (PHA-739358); JNJ-770621; MLN8054(N-{2-[6-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidine-2-ylamino)-(1S,4R)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl]-2-oxo-ethyl}-acetamide)(PF-03814735); PHA-680632; tozasertib (VX680 or MK-0457, CAS639089-54-6); and ZM447439(N-[4-[[6-Methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino]phenyl]benzamide,CAS 331771-20-1). Additional examples of an aurora inhibitor are knownin the art.

The phrase “dysregulation of an AXL gene, an AXL protein, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a chromosomal translocation that results in theexpression of a fusion protein including an AXL kinase domain and afusion partner, a mutation in an AXL gene that results in the expressionan AXL protein that includes a deletion of at least one amino acid ascompared to a wildtype AXL protein, a mutation in an AXL gene thatresults in the expression of an AXL protein with one or more pointmutations as compared to a wildtype AXL protein, a mutation in an AXLgene that results in the expression of an AXL protein with at least oneinserted amino acid as compared to a wildtype AXL protein, a geneduplication that results in an increased level of AXL protein in a cell,or a mutation in a regulatory sequence (e.g., a promoter and/orenhancer) that results in an increased level of AXL protein in a cell),an alternative spliced version of an AXL mRNA that results in an AXLprotein having a deletion of at least one amino acid in the AXL proteinas compared to the wild-type AXL protein), or increased expression(e.g., increased levels) of a wildtype AXL protein in a mammalian celldue to aberrant cell signaling and/or dysregulated autocrine/paracrinesignaling (e.g., as compared to a control non-cancerous cell). Asanother example, a dysregulation of an AXL gene, an AXL protein, orexpression or activity, or level of any of the same, can be a mutationin an AXL gene that encodes an AXL protein that is constitutively activeor has increased activity as compared to a protein encoded by an AXLgene that does not include the mutation. For example, a dysregulation ofan AXL gene, an AXL protein, or expression or activity, or level of anyof the same, can be the result of a gene or chromosome translocationwhich results in the expression of a fusion protein that contains afirst portion of an AXL protein that includes a functional kinasedomain, and a second portion of a partner protein (i.e., that is notAXL). In some examples, dysregulation of an AXL gene, an AXL protein, orexpression or activity or level of any of the same can be a result of agene translocation of one AXL gene with another non-AXLgene.

Non-limiting examples of an AXL inhibitor include bemcetinib (R428,BGB324); amuvatinib (MP470); cabozantinib; DCC-2036; DS-1205;gilteritinib (ASP2215); NPS-1034; RXDX-106; and TP-0903. Additionalexamples of an AXL inhibitor are known in the art.

The phrase “dysregulation of a BRAF gene, a BRAF protein, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a chromosomal translocation that results in theexpression of a fusion protein including a BRAF kinase domain and afusion partner, a mutation in a BRAF gene that results in the expressionof a BRAF protein that includes a deletion of at least one amino acid ascompared to a wild type BRAF protein, a mutation in a BRAF gene thatresults in the expression of a BRAF protein with one or more pointmutations as compared to a wildtype BRAF protein, a mutation in a BRAFgene that results in the expression of a BRAF protein with at least oneinserted amino acid as compared to a wildtype BRAF protein, a geneduplication that results in an increased level of BRAF protein in acell, or a mutation in a regulatory sequence (e.g., a promoter and/orenhancer) that results in an increased level of BRAF protein in a cell),an alternative spliced version of a BRAF mRNA that results in a BRAFprotein having a deletion of at least one amino acid in the BRAF proteinas compared to the wild-type BRAF protein), or increased expression(e.g., increased levels) of a wildtype BRAF protein in a mammalian celldue to aberrant cell signaling and/or dysregulated autocrine/paracrinesignaling (e.g., as compared to a control non-cancerous cell). Asanother example, a dysregulation of a BRAF gene, a BRAF protein, orexpression or activity, or level of any of the same, can be a mutationin a BRAF gene that encodes a BRAF protein that is constitutively activeor has increased activity as compared to a protein encoded by a BRAFgene that does not include the mutation. For example, a dysregulation ofa BRAF gene, a BRAF protein, or expression or activity, or level of anyof the same, can be the result of a gene or chromosome translocationwhich results in the expression of a fusion protein that contains afirst portion of a BRAF protein that includes a functional kinasedomain, and a second portion of a partner protein (i.e., that is notBRAF). In some examples, dysregulation of a BRAF gene, a BRAF protein,or expression or activity or level of any of the same can be a result ofa gene translocation of one BRAF gene with another non-BRAF gene.

Non-limiting examples of a BRAF inhibitor include((S)-2-{4-[3-(5-chloro-2-fluoro-3-methanesulfonylamino-phenyl)-1-isopropyl-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-1-methyl-ethyl)-carbamicacid methyl ester; BMS-908662 (Bristol-Meyers Squibb); dabrafenib;GDC-0879; GSK2118436 (GlaxoSmithKline); LGX818 (Novartis); PLX3603(Hofmann-LaRoche); PLX-4720; RAF265 (Novartis); R05185426(Hofmann-LaRoche); sorafenib tosylate; and vemurafenib (also calledRG7204 or PLX4032). Additional examples of a BRAF inhibitor are known inthe art.

The phrase “dysregulation of a CDK gene, a CDK protein, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a chromosomal translocation that results in theexpression of a fusion protein including a CDK kinase domain and afusion partner, a mutation in a CDK gene that results in the expressionof a CDK protein that includes a deletion of at least one amino acid ascompared to a wildtype CDK protein, a mutation in a CDK gene thatresults in the expression of a CDK protein with one or more pointmutations as compared to a wildtype CDK protein, a mutation in a CDKgene that results in the expression of a CDK protein with at least oneinserted amino acid as compared to a wildtype CDK protein, a geneduplication that results in an increased level of CDK protein in a cell,or a mutation in a regulatory sequence (e.g., a promoter and/orenhancer) that results in an increased level of CDK protein in a cell),an alternative spliced version of a CDK mRNA that results in a CDKprotein having a deletion of at least one amino acid in the CDK proteinas compared to the wild-type CDK protein), or increased expression(e.g., increased levels) of a wildtype CDK protein in a mammalian celldue to aberrant cell signaling and/or dysregulated autocrine/paracrinesignaling (e.g., as compared to a control non-cancerous cell). Asanother example, a dysregulation of a CDK gene, a CDK protein, orexpression or activity, or level of any of the same, can be a mutationin a CDK gene that encodes a CDK protein that is constitutively activeor has increased activity as compared to a protein encoded by a CDK genethat does not include the mutation. For example, a dysregulation of aCDK gene, a CDK protein, or expression or activity, or level of any ofthe same, can be the result of a gene or chromosome translocation whichresults in the expression of a fusion protein that contains a firstportion of a CDK protein that includes a functional kinase domain, and asecond portion of a partner protein (i.e., that is not CDK). In someexamples, dysregulation of a CDK gene, a CDK protein, or expression oractivity or level of any of the same can be a result of a genetranslocation of one CDK gene with another non-CDK gene.

Non-limiting examples of a CDK inhibitor include abemaciclib(LY2835219); AG-024322(5-[3-(4,6-Difluoro-1H-benzimidazol-2-yl)-1H-indazol-5-yl]-N-ethyl-4-methyl-3-pyridinemethanamine,CAS 837364-57-5); Aloisine A; alvocidib(2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methyl-4-piperidinyl]-4-chromenone,flavopiridol, HMR-1275); AT7519(4-(2,6-Dichlorobenzoylamino)-1H-pyrazole-3-carboxylic acidN-(piperidin-4-yl)amide, CAS 844442-38-2); AZD5438(4-[2-Methyl-1-(1-methylethyl)-1H-imidazol-5-yl]-N-[4-(methylsulfonyl)phenyl]-2-pyrimidinamine,CAS 602306-29-6); BAY 10000394((2R,3R)-3-[[2-[[3-[[S(R)]-S-cyclopropylsulfonimidoyl]-phenyl]amino]-5-(trifluoromethyl)-4-pyrimidinyl]oxy]-2-butanol);BMS 387032(N-[5-[[(5-tert-Butyloxazol-2-yl)methyl]thio]thiazol-2-yl]piperidine-4-carboxamide,CAS 345627-80-7); Dinacidib (SCH-727965); G1T38; Indisulam (E7070);JNJ-770621; P276-000(2-(2-Chlorophenyl)-5,7-dihydroxy-8-[(2R,3S)-2-(hydroxymethyl)-1-methyl-3-pyrrolidinyl]-4H-1-benzopyran-4-one,hydrochloride, CAS 920113-03-7); palbocidib (PD0332991,6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(1-piperazinyl)-2-pyridinyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one);ribocidib(LEE011,7-cyclopentyl-N,N-dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide);Selicidib (roscovitine or CYC202); trilacidib (G1T28); and vorucidib.Additional examples of a CDK inhibitor are known in the art.

The phrase “dysregulation of an EGFR gene, an EGFR protein, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a chromosomal translocation that results in theexpression of a fusion protein including an EGFR kinase domain and afusion partner, a mutation in an EGFR gene that results in theexpression of an EGFR protein that includes a deletion of at least oneamino acid as compared to a wildtype EGFR protein, a mutation in an EGFRgene that results in the expression of an EGFR protein with one or morepoint mutations as compared to a wildtype EGFR protein, a mutation in anEGFR gene that results in the expression of an EGFR protein with atleast one inserted amino acid as compared to a wildtype EGFR protein, agene duplication that results in an increased level of EGFR protein in acell, or a mutation in a regulatory sequence (e.g., a promoter and/orenhancer) that results in an increased level of EGFR protein in a cell),an alternative spliced version of a EGFR mRNA that results in an EGFRprotein having a deletion of at least one amino acid in the EGFR proteinas compared to the wild-type EGFR protein), or increased expression(e.g., increased levels) of a wildtype EGFR protein in a mammalian celldue to aberrant cell signaling and/or dysregulated autocrine/paracrinesignaling (e.g., as compared to a control non-cancerous cell). Asanother example, a dysregulation of an EGFR gene, an EGFR protein, orexpression or activity, or level of any of the same, can be a mutationin an EGFR gene that encodes an EGFR protein that is constitutivelyactive or has increased activity as compared to a protein encoded by anEGFR gene that does not include the mutation. For example, adysregulation of an EGFR gene, an EGFR protein, or expression oractivity, or level of any of the same, can be the result of a gene orchromosome translocation which results in the expression of a fusionprotein that contains a first portion of a EGFR protein that includes afunctional kinase domain, and a second portion of a partner protein(i.e., that is not EGFR). In some examples, dysregulation of an EGFRgene, an EGFR protein, or expression or activity or level of any of thesame can be a result of a gene translocation of one EGFR gene withanother non-EGFR gene.

Non-limiting examples of an EGFR inhibitor include AC0010; AEE788;afatinib; AP26113; ASP8273; avitinib; AZD3759; BIBX-1382(N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine);BMS-690514; brigatinib; brivanib; canertinib; Cap-701; CGP 59326A;CHMFL-EGFR-202; CL-387785; CUDC-101; dacomitinib; EAI045; EGF816;erlotinib; gefitinib (ZD1839); GNS-1481; GNS-1486; Gö6976; GW-2016(GW-572016); HS-10296; icotinib; KU004; lapatinib; nazartinib;neratinib; olmutinib (HM61713, BI 1482694); osimertinib (AZD9291);pelitinib (EKB-569;(E)-N-[4-(3-chloro-4-fluoroanilino)-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide);PD156393; PD 183805 (C11033,N-[4-(3-chloro-4-fluoroanilino)-7-(3-morpholin-4-ylpropoxy)quinazolin-6-yl]prop-2-enamide);PF-06747775; PKC412; PKI-166((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol);(R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine);poziotinib (HM781-36); pyrotinib (HTI-1001); rocilentinib (CO-1686);sapitinib; tyrphostin AG (AG1478); vandetanib; varlitinib; XL647; ZM105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline); 7C3; ABX-EGF;cetuximab; depatuxizumab mafodotin (ABT-414); EMD55900; GA201 (RG7160);IMC-11F8; MAb 225 (ATCC CRL 8508); MAb 455 (ATCC CRL HB8507); MAb 528(ATCC CRL 8509); MAb 579 (ATCC CRL HB 8506); mAb806; mAb806 (humanized);matuzumab (EMD7200); MDX-447; nimotuzumab; panitumumab; Pertuzumab;reshaped human 225 (H225); and zalutumumab. Additional examples of anEGFR inhibitor are known in the art.

The phrase “dysregulation of an ERK gene, an ERK protein, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a chromosomal translocation that results in theexpression of a fusion protein including an ERK kinase domain and afusion partner, a mutation in an ERK gene that results in the expressionof an ERK protein that includes a deletion of at least one amino acid ascompared to a wild type ERK protein, a mutation in an ERK gene thatresults in the expression of an ERK protein with one or more pointmutations as compared to a wildtype ERK protein, a mutation in an ERKgene that results in the expression of an ERK protein with at least oneinserted amino acid as compared to a wildtype ERK protein, a geneduplication that results in an increased level of ERK protein in a cell,or a mutation in a regulatory sequence (e.g., a promoter and/orenhancer) that results in an increased level of ERK protein in a cell),an alternative spliced version of a ERK mRNA that results in an ERKprotein having a deletion of at least one amino acid in the ERK proteinas compared to the wild-type ERK protein), or increased expression(e.g., increased levels) of a wildtype ERK protein in a mammalian celldue to aberrant cell signaling and/or dysregulated autocrine/paracrinesignaling (e.g., as compared to a control non-cancerous cell). Asanother example, a dysregulation of an ERK gene, an ERK protein, orexpression or activity, or level of any of the same, can be a mutationin an ERK gene that encodes an ERK protein that is constitutively activeor has increased activity as compared to a protein encoded by an ERKgene that does not include the mutation. For example, a dysregulation ofan ERK gene, an ERK protein, or expression or activity, or level of anyof the same, can be the result of a gene or chromosome translocationwhich results in the expression of a fusion protein that contains afirst portion of a ERK protein that includes a functional kinase domain,and a second portion of a partner protein (i.e., that is not ERK). Insome examples, dysregulation of an ERK gene, an ERK protein, orexpression or activity or level of any of the same can be a result of agene translocation of one ERK gene with another non-ERK gene.

Non-limiting examples of an ERK inhibitor include 25-OH-D3-3-BE (B3CD,bromoacetoxycalcidiol); 5-7-Oxozeaenol; 5-iodotubercidin; AEZ-131(AEZS-131); AEZS-136; ARRY-142886; ASN007; AZ-13767370; BAY 43-9006;BL-EI-001; CC-90003; FR148083; FR-180204; FRI-20 (ON-01060); GDC-0994(RG-7482); KO-947; LTT-462; LY294002; LY-3214996; MK-8353 (SCH900353);ONC201; PD0325901; PD184352; PD98059; SB239063; SCH772984; SP600125;U0126; ulixertinib (BVD-523); VTX-11e; and wortmannin. Additionalexamples of an ERK inhibitor are known in the art.

The phrase “dysregulation of a FLT3 gene, a FLT3 protein, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a chromosomal translocation that results in theexpression of a fusion protein including a FLT3 kinase domain and afusion partner, a mutation in a FLT3 gene that results in the expressionof a FLT3 protein that includes a deletion of at least one amino acid ascompared to a wild type FLT3 protein, a mutation in a FLT3 gene thatresults in the expression of a FLT3 protein with one or more pointmutations as compared to a wildtype FLT3 protein, a mutation in a FLT3gene that results in the expression of a FLT3 protein with at least oneinserted amino acid as compared to a wildtype FLT3 protein, a geneduplication that results in an increased level of FLT3 protein in acell, or a mutation in a regulatory sequence (e.g., a promoter and/orenhancer) that results in an increased level of FLT3 protein in a cell),an alternative spliced version of a FLT3 mRNA that results in a FLT3protein having a deletion of at least one amino acid in the FLT3 proteinas compared to the wild-type FLT3 protein), or increased expression(e.g., increased levels) of a wildtype FLT3 protein in a mammalian celldue to aberrant cell signaling and/or dysregulated autocrine/paracrinesignaling (e.g., as compared to a control non-cancerous cell). Asanother example, a dysregulation of a FLT3 gene, a FLT3 protein, orexpression or activity, or level of any of the same, can be a mutationin a FLT3 gene that encodes a FLT3 protein that is constitutively activeor has increased activity as compared to a protein encoded by a FLT3gene that does not include the mutation. For example, a dysregulation ofa FLT3 gene, a FLT3 protein, or expression or activity, or level of anyof the same, can be the result of a gene or chromosome translocationwhich results in the expression of a fusion protein that contains afirst portion of a FLT3 protein that includes a functional kinasedomain, and a second portion of a partner protein (i.e., that is notFLT3). In some examples, dysregulation of a FLT3 gene, a FLT3 protein,or expression or activity or level of any of the same can be a result ofa gene translocation of one FLT3 gene with another non-FLT3 gene.

Non-limiting examples of a FLT3 inhibitor include AC220(N-(5-tert-Butyl-isoxazol-3-yl)-N′-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}ureadihydrochloride); CEP-701; crenolanib; gilteritinib (ASP2215); KW-2449;lestaurtinib; midostaruin (PKC 412); quizartinib; SB1518(11-(2-Pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-l(25),2(26),3,5,8,10,12(27),16,21,23-decaene);SB1578; semaxinib (SU5416); sunitinib (SU11248); and tandutinib(MLN518/CT53518). Additional examples of a FLT3 inhibitor are known inthe art.

The phrase “dysregulation of a HER2 gene, a HER2 protein, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a chromosomal translocation that results in theexpression of a fusion protein including a HER2 kinase domain and afusion partner, a mutation in a HER2 gene that results in the expressionof a HER2 protein that includes a deletion of at least one amino acid ascompared to a wildtype HER2 protein, a mutation in a HER2 gene thatresults in the expression of a HER2 protein with one or more pointmutations as compared to a wildtype HER2 protein, a mutation in a HER2gene that results in the expression of a HER2 protein with at least oneinserted amino acid as compared to a wildtype HER2 protein, a geneduplication that results in an increased level of HER2 protein in acell, or a mutation in a regulatory sequence (e.g., a promoter and/orenhancer) that results in an increased level of HER2 protein in a cell),an alternative spliced version of a HER2 mRNA that results in a HER2protein having a deletion of at least one amino acid in the HER2 proteinas compared to the wild-type HER2 protein), or increased expression(e.g., increased levels) of a wildtype HER2 protein in a mammalian celldue to aberrant cell signaling and/or dysregulated autocrine/paracrinesignaling (e.g., as compared to a control non-cancerous cell). Asanother example, a dysregulation of a HER2 gene, a HER2 protein, orexpression or activity, or level of any of the same, can be a mutationin a HER2 gene that encodes a HER2 protein that is constitutively activeor has increased activity as compared to a protein encoded by a HER2gene that does not include the mutation. For example, a dysregulation ofa HER2 gene, a HER2 protein, or expression or activity, or level of anyof the same, can be the result of a gene or chromosome translocationwhich results in the expression of a fusion protein that contains afirst portion of a HER2 protein that includes a functional kinasedomain, and a second portion of a partner protein (i.e., that is notHER2). In some examples, dysregulation of a HER2 gene, a HER2 protein,or expression or activity or level of any of the same can be a result ofa gene translocation of one HER2 gene with another non-HER2 gene.

Non-limiting examples of a HER2 inhibitor include AEE788; afatinib (BIBW2992); AP32788 (TAK-788); ARRY-334543 (ARRY-543, ASLAN001); AST1306;AZD8961; BMS-599626 (AC480); BMS-690514; canertinib (PD 183805, C11033,N-[4-(3-chloro-4-fluoroanilino)-7-(3-morpholin-4-ylpropoxy)quinazolin-6-yl]prop-2-enamide);CP-654577; CP724714; CUDC101; D-69491; D-70166; dacomitinib(PF-00299804); DS8201-a; emodin; erlontinib; gefitinib; GW-2016(GW-572016); HKI-357; KU004; lapatinib; laptinib ditosylate; MM-111;mubritinib (TAK-165); neratinib (HKI-257); pelitinib (EKB-569,(E)-N-[4-(3-chloro-4-fluoroanilino)-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide);PKI-166((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol);(R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine);poziotinib (HM781-36); pyrotinib (HTI-1001); sapitinib (AZD8930);TAK285; TAS0728; tesevatinib (K_(D)019, XL647, PRIM-001); tucatinib(ONT-380, ARRY-380); varlitinib (ASLAN001, ARRY-543); 7C3; anti-HER2CAR-T therapy; cetuximab; DXL702; E75; HER2Bi-Armed Activated T Cells;HER2-BsAb; HER2-Peptid-Vakzine; hersintuzumab; herstatin; margetuximab;MEDI4276; MI130004; NeuVax; osidem; paitumumab; pertuzumab; PX-104.1;SYD985; trastuzumab; trastuzumab emtansine (KADCYLA®, T-DM1);trastuzumab-dkst (OGIVRI®); zemab; and ZW25. Additional examples of aHER2 inhibitor are known in the art.

The phrase “dysregulation of a HER3 gene, a HER3 protein, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a chromosomal translocation that results in theexpression of a fusion protein including a HER3 kinase domain and afusion partner, a mutation in a HER3 gene that results in the expressionof a HER3 protein that includes a deletion of at least one amino acid ascompared to a wildtype HER3 protein, a mutation in a HER3 gene thatresults in the expression of a HER3 protein with one or more pointmutations as compared to a wildtype HER3 protein, a mutation in a HER3gene that results in the expression of a HER3 protein with at least oneinserted amino acid as compared to a wildtype HER3 protein, a geneduplication that results in an increased level of HER3 protein in acell, or a mutation in a regulatory sequence (e.g., a promoter and/orenhancer) that results in an increased level of HER3 protein in a cell),an alternative spliced version of a HER3 mRNA that results in a HER3protein having a deletion of at least one amino acid in the HER3 proteinas compared to the wild-type HER3 protein), or increased expression(e.g., increased levels) of a wildtype HER3 protein in a mammalian celldue to aberrant cell signaling and/or dysregulated autocrine/paracrinesignaling (e.g., as compared to a control non-cancerous cell). Asanother example, a dysregulation of a HER3 gene, a HER3 protein, orexpression or activity, or level of any of the same, can be a mutationin a HER3 gene that encodes a HER3 protein that is constitutively activeor has increased activity as compared to a protein encoded by a HER3gene that does not include the mutation. For example, a dysregulation ofa HER3 gene, a HER3 protein, or expression or activity, or level of anyof the same, can be the result of a gene or chromosome translocationwhich results in the expression of a fusion protein that contains afirst portion of a HER3 protein that includes a functional kinasedomain, and a second portion of a partner protein (i.e., that is notHER3). In some examples, dysregulation of a HER3 gene, a HER3 protein,or expression or activity or level of any of the same can be a result ofa gene translocation of one HER3 gene with another non-HER3 gene.

Non-limiting examples of a HER3 inhibitor include AST1306; AZD8961;gefitinib; neratinib; poziotinib (HM781-36); sapitinib; varlintinib(ARRY-334543, ARRY-543, ASLAN001); AV-203; duligotuzumab; istiratumab(MM-141); UM716; lumretuzumab; patritumab (U3-1287); pertuzumab;REGN1400; seribantumab (MM-121); TK-A3; and TK-A4. Additional examplesof a HER3 inhibitor are known in the art.

The phrase “dysregulation of a HER4 gene, a HER4 protein, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a chromosomal translocation that results in theexpression of a fusion protein including a HER4 kinase domain and afusion partner, a mutation in a HER4 gene that results in the expressionof a HER4 protein that includes a deletion of at least one amino acid ascompared to a wild type HER4 protein, a mutation in a HER4 gene thatresults in the expression of a HER4 protein with one or more pointmutations as compared to a wildtype HER4 protein, a mutation in a HER4gene that results in the expression of a HER4 protein with at least oneinserted amino acid as compared to a wildtype HER4 protein, a geneduplication that results in an increased level of HER4 protein in acell, or a mutation in a regulatory sequence (e.g., a promoter and/orenhancer) that results in an increased level of HER4 protein in a cell),an alternative spliced version of a HER4 mRNA that results in a HER4protein having a deletion of at least one amino acid in the HER4 proteinas compared to the wild-type HER4 protein), or increased expression(e.g., increased levels) of a wildtype HER4 protein in a mammalian celldue to aberrant cell signaling and/or dysregulated autocrine/paracrinesignaling (e.g., as compared to a control non-cancerous cell). Asanother example, a dysregulation of a HER4 gene, a HER4 protein, orexpression or activity, or level of any of the same, can be a mutationin a HER4 gene that encodes a HER4 protein that is constitutively activeor has increased activity as compared to a protein encoded by a HER4gene that does not include the mutation. For example, a dysregulation ofa HER4 gene, a HER4 protein, or expression or activity, or level of anyof the same, can be the result of a gene or chromosome translocationwhich results in the expression of a fusion protein that contains afirst portion of a HER4 protein that includes a functional kinasedomain, and a second portion of a partner protein (i.e., that is notHER4). In some examples, dysregulation of a HER4 gene, a HER4 protein,or expression or activity or level of any of the same can be a result ofa gene translocation of one HER4 gene with another non-HER4 gene.

Non-limiting examples of a HER4 inhibitor include AST1306; BMS-599626(AC480); BMS-690514; canertinib (PD 183805, C11033,N-[4-(3-chloro-4-fluoroanilino)-7-(3-morpholin-4-ylpropoxy)quinazolin-6-yl]prop-2-enamide);and pelitinib (EKB-569,(E)-N-[4-(3-chloro-4-fluoroanilino)-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide).Additional examples of a HER4 inhibitor are known in the art.

The phrase “dysregulation of an IGFR gene, an IGFR protein, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a chromosomal translocation that results in theexpression of a fusion protein including an IGFR kinase domain and afusion partner, a mutation in an IGFR gene that results in theexpression of an IGFR protein that includes a deletion of at least oneamino acid as compared to a wildtype IGFR protein, a mutation in an IGFRgene that results in the expression of an IGFR protein with one or morepoint mutations as compared to a wildtype IGFR protein, a mutation in anIGFR gene that results in the expression of an IGFR protein with atleast one inserted amino acid as compared to a wildtype IGFR protein, agene duplication that results in an increased level of IGFR protein in acell, or a mutation in a regulatory sequence (e.g., a promoter and/orenhancer) that results in an increased level of IGFR protein in a cell),an alternative spliced version of an IGFR mRNA that results in an IGFRprotein having a deletion of at least one amino acid in the IGFR proteinas compared to the wild-type IGFR protein), or increased expression(e.g., increased levels) of a wildtype IGFR protein in a mammalian celldue to aberrant cell signaling and/or dysregulated autocrine/paracrinesignaling (e.g., as compared to a control non-cancerous cell). Asanother example, a dysregulation of an IGFR gene, an IGFR protein, orexpression or activity, or level of any of the same, can be a mutationin an IGFR gene that encodes an IGFR protein that is constitutivelyactive or has increased activity as compared to a protein encoded by anIGFR gene that does not include the mutation. For example, adysregulation of an IGFR gene, an IGFR protein, or expression oractivity, or level of any of the same, can be the result of a gene orchromosome translocation which results in the expression of a fusionprotein that contains a first portion of a IGFR protein that includes afunctional kinase domain, and a second portion of a partner protein(i.e., that is not IGFR). In some examples, dysregulation of an IGFRgene, an IGFR protein, or expression or activity or level of any of thesame can be a result of a gene translocation of one IGFR gene withanother non-IGFR gene.

A non-limiting example of an IGFR inhibitor is lisitinib (OSI-906).Additional examples of an IGFR inhibitor are known in the art.

The phrase “dysregulation of a JAK1 gene, a JAK1 protein, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a chromosomal translocation that results in theexpression of a fusion protein including a JAK1 kinase domain and afusion partner, a mutation in a JAK1 gene that results in the expressionof a JAK1 protein that includes a deletion of at least one amino acid ascompared to a wildtype JAK1 protein, a mutation in a JAK1 gene thatresults in the expression of a JAK1 protein with one or more pointmutations as compared to a wildtype JAK1 protein, a mutation in a JAK1gene that results in the expression of a JAK1 protein with at least oneinserted amino acid as compared to a wildtype JAK1 protein, a geneduplication that results in an increased level of JAK1 protein in acell, or a mutation in a regulatory sequence (e.g., a promoter and/orenhancer) that results in an increased level of JAK1 protein in a cell),an alternative spliced version of a JAK1 mRNA that results in a JAK1protein having a deletion of at least one amino acid in the JAK1 proteinas compared to the wild-type JAK1 protein), or increased expression(e.g., increased levels) of a wildtype JAK1 protein in a mammalian celldue to aberrant cell signaling and/or dysregulated autocrine/paracrinesignaling (e.g., as compared to a control non-cancerous cell). Asanother example, a dysregulation of a JAK1 gene, a JAK1 protein, orexpression or activity, or level of any of the same, can be a mutationin a JAK1 gene that encodes a JAK1 protein that is constitutively activeor has increased activity as compared to a protein encoded by a JAK1gene that does not include the mutation. For example, a dysregulation ofa JAK1 gene, a JAK1 protein, or expression or activity, or level of anyof the same, can be the result of a gene or chromosome translocationwhich results in the expression of a fusion protein that contains afirst portion of a JAK1 protein that includes a functional kinasedomain, and a second portion of a partner protein (i.e., that is notJAK1). In some examples, dysregulation of a JAK1 gene, a JAK1 protein,or expression or activity or level of any of the same can be a result ofa gene translocation of one JAK1 gene with another non-JAK1 gene.

Non-limiting examples of a JAK1 inhibitor include baricitinib(OLUMIANT®, LY-3009104, INCB-28050); filgotinib (G-146034, GLPG-0634);itacitinib (INCB039110); momelotinib (GS-0387, CYT-387); oclacitinib;peficitinib (ASP015K, JNJ-54781532); PF-04965842(N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide);ruxolitinib (INCB018424); solcitinib (GSK2586184); and upadacitinib(ABT-494). Additional examples of a JAK1 inhibitor are known in the art.

Additional JAK family targeted therapeutics include those described inU.S. Pat. Nos. 8,604,043,7,834,022,8,486,902,8,530,485,7,598,257,8,541,425,8,410,265,9,987,276,and 9,949,971, and U.S. Patent Application Publication Nos. 2018/0051036A1, 2010/0298355 A1, 2008/0312258 A1, 2011/0082159 A1, 2011/0086810 A1,2013/0345157 A1, 2014/0018374 A1, 2014/0005210 A1, 2011/0223210 A1,2011/0224157 A1, 2007/0135461 A1, 2010/0022522 A1, 2013/0253193 A1,2013/0253191 A1, 2013/0253190 A1, 2010/0190981 A1, 2013/0338134 A1,2008/0312259 A1, 2014/0094477 A1, and 2014/0094476 A1, the disclosuresof which are incorporated by reference herein.

The phrase “dysregulation of a JAK2 gene, a JAK2 protein, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a chromosomal translocation that results in theexpression of a fusion protein including a JAK2 kinase domain and afusion partner, a mutation in a JAK2 gene that results in the expressionof a JAK2 protein that includes a deletion of at least one amino acid ascompared to a wild type JAK2 protein, a mutation in a JAK2 gene thatresults in the expression of a JAK2 protein with one or more pointmutations as compared to a wildtype JAK2 protein, a mutation in a JAK2gene that results in the expression of a JAK2 protein with at least oneinserted amino acid as compared to a wildtype JAK2 protein, a geneduplication that results in an increased level of JAK2 protein in acell, or a mutation in a regulatory sequence (e.g., a promoter and/orenhancer) that results in an increased level of JAK2 protein in a cell),an alternative spliced version of a JAK2 mRNA that results in a JAK2protein having a deletion of at least one amino acid in the JAK2 proteinas compared to the wild-type JAK2 protein), or increased expression(e.g., increased levels) of a wildtype JAK2 protein in a mammalian celldue to aberrant cell signaling and/or dysregulated autocrine/paracrinesignaling (e.g., as compared to a control non-cancerous cell). Asanother example, a dysregulation of a JAK2 gene, a JAK2 protein, orexpression or activity, or level of any of the same, can be a mutationin a JAK2 gene that encodes a JAK2 protein that is constitutively activeor has increased activity as compared to a protein encoded by a JAK2gene that does not include the mutation. For example, a dysregulation ofa JAK2 gene, a JAK2 protein, or expression or activity, or level of anyof the same, can be the result of a gene or chromosome translocationwhich results in the expression of a fusion protein that contains afirst portion of a JAK2 protein that includes a functional kinasedomain, and a second portion of a partner protein (i.e., that is notJAK2). In some examples, dysregulation of a JAK2 gene, a JAK2 protein,or expression or activity or level of any of the same can be a result ofa gene translocation of one JAK2 gene with another non-JAK2 gene.

Non-limiting examples of a JAK2 inhibitor include pacritinib (SB1578);atiprimod; baricitinib (OLUMIANT® LY-3009104, INCB-28050); fedratinib(SAR302503); gandotinib (LY-2784544); lestaurtinib (CEP-701);momelotinib (GS-0387, CYT-387); oclacitinib; peficitinib (ASP015K,JNJ-54781532); ruxolitinib (INCB018424); and SB1518(11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene).Additional examples of a JAK2 inhibitor are known in the art.

The phrase “dysregulation of a JAK3 gene, a JAK3 protein, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a chromosomal translocation that results in theexpression of a fusion protein including a JAK3 kinase domain and afusion partner, a mutation in a JAK3 gene that results in the expressionof a JAK3 protein that includes a deletion of at least one amino acid ascompared to a wildtype JAK3 protein, a mutation in a JAK3 gene thatresults in the expression of a JAK3 protein with one or more pointmutations as compared to a wildtype JAK3 protein, a mutation in a JAK3gene that results in the expression of a JAK3 protein with at least oneinserted amino acid as compared to a wildtype JAK3 protein, a geneduplication that results in an increased level of JAK3 protein in acell, or a mutation in a regulatory sequence (e.g., a promoter and/orenhancer) that results in an increased level of JAK3 protein in a cell),an alternative spliced version of a JAK3 mRNA that results in a JAK3protein having a deletion of at least one amino acid in the JAK3 proteinas compared to the wild-type JAK3 protein), or increased expression(e.g., increased levels) of a wildtype JAK3 protein in a mammalian celldue to aberrant cell signaling and/or dysregulated autocrine/paracrinesignaling (e.g., as compared to a control non-cancerous cell). Asanother example, a dysregulation of a JAK3 gene, a JAK3 protein, orexpression or activity, or level of any of the same, can be a mutationin a JAK3 gene that encodes a JAK3 protein that is constitutively activeor has increased activity as compared to a protein encoded by a JAK3gene that does not include the mutation. For example, a dysregulation ofa JAK3 gene, a JAK3 protein, or expression or activity, or level of anyof the same, can be the result of a gene or chromosome translocationwhich results in the expression of a fusion protein that contains afirst portion of a JAK3 protein that includes a functional kinasedomain, and a second portion of a partner protein (i.e., that is notJAK3). In some examples, dysregulation of a JAK3 gene, a JAK3 protein,or expression or activity or level of any of the same can be a result ofa gene translocation of one JAK3 gene with another non-JAK3 gene.

Non-limiting examples of a JAK3 inhibitor include atiprimod; JANEX-3(4-(3′-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline); peficitinib(ASP015K, JNJ-54781532); and tofacitinib. Additional examples of a JAK3inhibitor are known in the art.

The phrase “dysregulation of a Kit gene, a Kit protein, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a chromosomal translocation that results in theexpression of a fusion protein including a Kit kinase domain and afusion partner, a mutation in a Kit gene that results in the expressionof a Kit protein that includes a deletion of at least one amino acid ascompared to a wildtype Kit protein, a mutation in a Kit gene thatresults in the expression of a Kit protein with one or more pointmutations as compared to a wildtype Kit protein, a mutation in a Kitgene that results in the expression of a Kit protein with at least oneinserted amino acid as compared to a wildtype Kit protein, a geneduplication that results in an increased level of Kit protein in a cell,or a mutation in a regulatory sequence (e.g., a promoter and/orenhancer) that results in an increased level of Kit protein in a cell),an alternative spliced version of a Kit mRNA that results in a Kitprotein having a deletion of at least one amino acid in the Kit proteinas compared to the wild-type Kit protein), or increased expression(e.g., increased levels) of a wildtype Kit protein in a mammalian celldue to aberrant cell signaling and/or dysregulated autocrine/paracrinesignaling (e.g., as compared to a control non-cancerous cell). Asanother example, a dysregulation of a Kit gene, a Kit protein, orexpression or activity, or level of any of the same, can be a mutationin a Kit gene that encodes a Kit protein that is constitutively activeor has increased activity as compared to a protein encoded by a Kit genethat does not include the mutation. For example, a dysregulation of aKit gene, a Kit protein, or expression or activity, or level of any ofthe same, can be the result of a gene or chromosome translocation whichresults in the expression of a fusion protein that contains a firstportion of a Kit protein that includes a functional kinase domain, and asecond portion of a partner protein (i.e., that is not Kit). In someexamples, dysregulation of a Kit gene, a Kit protein, or expression oractivity or level of any of the same can be a result of a genetranslocation of one Kit gene with another non-Kit gene.

Non-limiting examples of a Kit inhibitor include AMG 706; amuvatinib(MP-470); APcK110; axitinib (AG-013736); AZD2932; dasatinib(BMS-354825); dovitinib (TKI-258, CHIR-258); EXEL-0862; imatinib;KI-328; masitinib (AB1010); midostaurin; MLN518; motesanib;N3-(6-aminopyridin-3-yl)-N1-(2-cyclopentylethyl)-4-methylisophthalamide;nilotinib; OSI-930; pazopanib (GW786034); pexidartinib (PLX3397);PKC412; PLX647; PP1; quizartinib (AC220); regorafenib (BAY 73-4506);semaxinib (SU 5416); sitravatinib (MGCD516); sorafenib; STI571; SU11248;SU9529; sunitinib; telatinib; tivozanib (AV-951); tyrphostin AG 1296;VX-322; and WBZ_4. Additional examples of a Kit inhibitor are known inthe art.

The phrase “dysregulation of a MEK gene, a MEK protein, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a chromosomal translocation that results in theexpression of a fusion protein including a MEK kinase domain and afusion partner, a mutation in a MEK gene that results in the expressionof a MEK protein that includes a deletion of at least one amino acid ascompared to a wild type MEK protein, a mutation in a MEK gene thatresults in the expression of a MEK protein with one or more pointmutations as compared to a wildtype MEK protein, a mutation in a MEKgene that results in the expression of a MEK protein with at least oneinserted amino acid as compared to a wildtype MEK protein, a geneduplication that results in an increased level of MEK protein in a cell,or a mutation in a regulatory sequence (e.g., a promoter and/orenhancer) that results in an increased level of MEK protein in a cell),an alternative spliced version of a MEK mRNA that results in a MEKprotein having a deletion of at least one amino acid in the MEK proteinas compared to the wild-type MEK protein), or increased expression(e.g., increased levels) of a wildtype MEK protein in a mammalian celldue to aberrant cell signaling and/or dysregulated autocrine/paracrinesignaling (e.g., as compared to a control non-cancerous cell). Asanother example, a dysregulation of a MEK gene, a MEK protein, orexpression or activity, or level of any of the same, can be a mutationin a MEK gene that encodes a MEK protein that is constitutively activeor has increased activity as compared to a protein encoded by a MEK genethat does not include the mutation. For example, a dysregulation of aMEK gene, a MEK protein, or expression or activity, or level of any ofthe same, can be the result of a gene or chromosome translocation whichresults in the expression of a fusion protein that contains a firstportion of a MEK protein that includes a functional kinase domain, and asecond portion of a partner protein (i.e., that is not MEK). In someexamples, dysregulation of a MEK gene, a MEK protein, or expression oractivity or level of any of the same can be a result of a genetranslocation of one MEK gene with another non-MEK gene.

Non-limiting examples of a MEK inhibitor include AS703026 (MSC1935369);AZD8330 (ARRY-424704); AZD6244 (ARRY-142866); BI-847325; binimetinib(MEKTOVI® MEK162); BIX02188; BIX02189; CH4987655; CH5126766; CI-1040;cobemetinib (COTELUC®, GDC-0973, XL-518); CS3006; EBI-1051; G-573;G8935; GDC-0623; hypothemycin; Myricetin; nobiletin; PD0325901;PD184161; PD184352 (CI-1040); PD318088; PD98059; PD325901; PD334581;pimasertib (AS-703026); refametinib (RDEA119, BAY 869766); R05126766;selumetinib (AZD6244); SHR7390; SL-327; TAK-733; trametinib (MEKINIST®GSK1120212); U0126; and WX-554. Additional examples of a MEK inhibitorare known in the art.

The phrase “dysregulation of a MET gene, a MET protein, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a chromosomal translocation that results in theexpression of a fusion protein including a MET kinase domain and afusion partner, a mutation in a MET gene that results in the expressiona MET protein that includes a deletion of at least one amino acid ascompared to a wildtype MET protein, a mutation in a MET gene thatresults in the expression of a MET protein with one or more pointmutations as compared to a wildtype MET protein, a mutation in a METgene that results in the expression of a MET protein with at least oneinserted amino acid as compared to a wildtype MET protein, a geneduplication that results in an increased level of MET protein in a cell,or a mutation in a regulatory sequence (e.g., a promoter and/orenhancer) that results in an increased level of MET protein in a cell),an alternative spliced version of a MET mRNA that results in a METprotein having a deletion of at least one amino acid in the MET proteinas compared to the wild-type MET protein), or increased expression(e.g., increased levels) of a wildtype MET protein in a mammalian celldue to aberrant cell signaling and/or dysregulated autocrine/paracrinesignaling (e.g., as compared to a control non-cancerous cell). Asanother example, a dysregulation of a MET gene, a MET protein, orexpression or activity, or level of any of the same, can be a mutationin a MET gene that encodes a MET protein that is constitutively activeor has increased activity as compared to a protein encoded by a MET genethat does not include the mutation. For example, a dysregulation of aMET gene, a MET protein, or expression or activity, or level of any ofthe same, can be the result of a gene or chromosome translocation whichresults in the expression of a fusion protein that contains a firstportion of a MET protein that includes a functional kinase domain, and asecond portion of a partner protein (i.e., that is not MET). In someexamples, dysregulation of a MET gene, a MET protein, or expression oractivity or level of any of the same can be a result of a genetranslocation of one MET gene with another non-MET gene.

Non-limiting examples of a MET inhibitor include (−)-Oleocanthal;ABBV-399; AL2846; AMG-208; AMG-337; AMG-458; amuvatinib (MP740,N-(1,3-benzodioxol-5-ylmethyl)-4-([1]benzofuro[3,2-d]pyrimidin-4-yl)piperazine-1-carbothioamide);APG-8361; ASLAN002; ASP-08001; ASP-08126; BAY-853474; BMS-754807;BMS-777607; BMS-794833; BMS-817378 (prodrug of BMS-794833); BPI-9016M;cabozantinib (XL184, BMS-907351); capmatinib(INCB28060,2-fluoro-N-methyl-4-{7-[(quinolin-6-yl)methyl]imidazo[1,2-b][1,2,4]triazin-2-yl}benzamide);crizotinib (PF-02341066); DCC-2036; DE60S; DP-3590; EMD-1204831;EMD-1214063; foretinib (GSK1363089, XL880); glesatinib (MGCD26S);glumetinib (SCC244); GM-604; golvatinib (E7050); HM-5016504; HS-10241;INCB028060; JNJ-38877605(6-(difluoro[6-(1-methyl-1H-pyrazol-4-yl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]methyl(quinoline); KRC-408; merestinib (LY2801653); MK-2461; MK8033; NK4;NPS-1034; NVP-BVU972; PF-04217903; PHA-665752; PLB1001; S49076;SAR-125844; savolitinib (volitinib, AZD6094, HMPL-504); sitravatinib(MGCD-S16); SGX-S23; SU11274; TAS-11S; tivatinib (ARQ197,(3R,4R)-3-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-2,5-pyrrolidinedione);tepotinib (EMD1214063, MSC2156119J); TQ-B3139; XL174;6-[di-fluoro(6-pyridin-4-yl[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl]quinoline;(E)-2-(1-(3-((7-fluoroquinolin-6-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)ethylidene)hydrazinecarboxamide;ABT-700; ABBV-399; ARGX-111; CE-355621; DN30; emibetuzumab; fidatuzumab(AV-299); HTI-1066; JNJ-61186372; LY2875358 (LA-480); LY3164530;onartuzumab (MetMAb); rilotumumab (AMG 102); SAIT301; Sym015; Tak-701;and YYB101. Additional examples of a MET inhibitor are known in the art.

The phrase “dysregulation of a mTOR gene, a mTOR protein, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a chromosomal translocation that results in theexpression of a fusion protein including a mTOR kinase domain and afusion partner, a mutation in a mTOR gene that results in the expressiona mTOR protein that includes a deletion of at least one amino acid ascompared to a wild type mTOR protein, a mutation in a mTOR gene thatresults in the expression of a mTOR protein with one or more pointmutations as compared to a wildtype mTOR protein, a mutation in a mTORgene that results in the expression of a mTOR protein with at least oneinserted amino acid as compared to a wildtype mTOR protein, a geneduplication that results in an increased level of mTOR protein in acell, or a mutation in a regulatory sequence (e.g., a promoter and/orenhancer) that results in an increased level of mTOR protein in a cell),an alternative spliced version of a mTOR mRNA that results in a mTORprotein having a deletion of at least one amino acid in the mTOR proteinas compared to the wild-type mTOR protein), or increased expression(e.g., increased levels) of a wildtype mTOR protein in a mammalian celldue to aberrant cell signaling and/or dysregulated autocrine/paracrinesignaling (e.g., as compared to a control non-cancerous cell). Asanother example, a dysregulation of a mTOR gene, a mTOR protein, orexpression or activity, or level of any of the same, can be a mutationin a mTOR gene that encodes a mTOR protein that is constitutively activeor has increased activity as compared to a protein encoded by a mTORgene that does not include the mutation. For example, a dysregulation ofa mTOR gene, a mTOR protein, or expression or activity, or level of anyof the same, can be the result of a gene or chromosome translocationwhich results in the expression of a fusion protein that contains afirst portion of a mTOR protein that includes a functional kinasedomain, and a second portion of a partner protein (i.e., that is notmTOR). In some examples, dysregulation of a mTOR gene, a mTOR protein,or expression or activity or level of any of the same can be a result ofa gene translocation of one mTOR gene with another non-mTOR gene.

Non-limiting examples of a mTOR inhibitor include anthracimycin;apitolisib (GDC-0980, RG7422); AZD-8055; BGT226 (NVP-BGT226); CC-115;CC-223; CZ415; dactolisib (BEZ235, NVP-BEZ235); DS7423; everolimus(RAD001); GDC-0084 (RG7666); GDC-0349; gedatolisib (PF-05212384,PKI-5587); GSK1059615; INK128; KU-0063794; LY3023414; MLN0128;omipalisib (GSK2126458, GSK458); OSI-027; OSU-53; Palomid 529 (P529);PF-04691502; PI-103; PKI-587; PP242; PQR309; ridafarolimus (AP-23573);sapanisertib (INK 128, MLN0128); SAR245409 (XL765); SF-1126; SF2523;sirolimus (rapamycin); SN32976; TAK228; temsirolimus (CCI-779, NSC683864); Torin 1; Torin 2; torkinib (PP242); umirolimus; vistusertib(AZD2014); voxtalisib (XL765, SAR245409); VS-5584 (SB2343); WAY-600;WYE-125132 (WYE-132); WYE-354; WYE-687; XL388; and zotarolimus(ABT-578). Additional examples of a mTOR inhibitor are known in the art.

The phrase “dysregulation of a PDGFRα gene, a PDGFRα protein, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a chromosomal translocation that results in theexpression of a fusion protein including a PDGFRα kinase domain and afusion partner, a mutation in a PDGFRα gene that results in theexpression a PDGFRα protein that includes a deletion of at least oneamino acid as compared to a wildtype PDGFRα protein, a mutation in aPDGFRα gene that results in the expression of a PDGFRα protein with oneor more point mutations as compared to a wildtype PDGFRα protein, amutation in a PDGFRα gene that results in the expression of a PDGFRαprotein with at least one inserted amino acid as compared to a wildtypePDGFRα protein, a gene duplication that results in an increased level ofPDGFRα protein in a cell, or a mutation in a regulatory sequence (e.g.,a promoter and/or enhancer) that results in an increased level of PDGFRαprotein in a cell), an alternative spliced version of a PDGFRα mRNA thatresults in a PDGFRα protein having a deletion of at least one amino acidin the PDGFRα protein as compared to the wild-type PDGFRα protein), orincreased expression (e.g., increased levels) of a wildtype PDGFRαprotein in a mammalian cell due to aberrant cell signaling and/ordysregulated autocrine/paracrine signaling (e.g., as compared to acontrol non-cancerous cell). As another example, a dysregulation of aPDGFRα gene, a PDGFRα protein, or expression or activity, or level ofany of the same, can be a mutation in a PDGFRα gene that encodes aPDGFRα protein that is constitutively active or has increased activityas compared to a protein encoded by a PDGFRα gene that does not includethe mutation. For example, a dysregulation of a PDGFRα gene, a PDGFRαprotein, or expression or activity, or level of any of the same, can bethe result of a gene or chromosome translocation which results in theexpression of a fusion protein that contains a first portion of a PDGFRαprotein that includes a functional kinase domain, and a second portionof a partner protein (i.e., that is not PDGFRα). In some examples,dysregulation of a PDGFRα gene, a PDGFRα protein, or expression oractivity or level of any of the same can be a result of a genetranslocation of one PDGFRα gene with another non-PDGFRα gene.

Non-limiting examples of a PDGFRα inhibitor include amuvatinib (MP470);axitinib (Inlyta®); imatinib (Gleevec®); masitinib; motesanibdiphosphate (AMG706, CAS 857876-30-3,N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide);nintedanib (BIBF1120, CAS 928326-83-4); pazopanib; quizartinib (AC220,CAS 950769-58-1); sorafenib (Nexavar®); and sunitinib. Additionalexamples of a PDGFRα inhibitor are known in the art.

The phrase “dysregulation of a PDGFRβ gene, a PDGFRβ protein, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a chromosomal translocation that results in theexpression of a fusion protein including a PDGFRβ kinase domain and afusion partner, a mutation in a PDGFRβ gene that results in theexpression a PDGFRβ protein that includes a deletion of at least oneamino acid as compared to a wildtype PDGFRβ protein, a mutation in aPDGFRβ gene that results in the expression of a PDGFRβ protein with oneor more point mutations as compared to a wildtype PDGFRβ protein, amutation in a PDGFRβ gene that results in the expression of a PDGFRβprotein with at least one inserted amino acid as compared to a wildtypePDGFRβ protein, a gene duplication that results in an increased level ofPDGFRβ protein in a cell, or a mutation in a regulatory sequence (e.g.,a promoter and/or enhancer) that results in an increased level of PDGFRβprotein in a cell), an alternative spliced version of a PDGFRβ mRNA thatresults in a PDGFRβ protein having a deletion of at least one amino acidin the PDGFRβ protein as compared to the wild-type PDGFRβ protein), orincreased expression (e.g., increased levels) of a wildtype PDGFRβprotein in a mammalian cell due to aberrant cell signaling and/ordysregulated autocrine/paracrine signaling (e.g., as compared to acontrol non-cancerous cell). As another example, a dysregulation of aPDGFRβ gene, a PDGFRβ protein, or expression or activity, or level ofany of the same, can be a mutation in a PDGFRβ gene that encodes aPDGFRβ protein that is constitutively active or has increased activityas compared to a protein encoded by a PDGFRβ gene that does not includethe mutation. For example, a dysregulation of a PDGFRβ gene, a PDGFRβprotein, or expression or activity, or level of any of the same, can bethe result of a gene or chromosome translocation which results in theexpression of a fusion protein that contains a first portion of a PDGFRβprotein that includes a functional kinase domain, and a second portionof a partner protein (i.e., that is not PDGFRβ). In some examples,dysregulation of a PDGFRβ gene, a PDGFRβ protein, or expression oractivity or level of any of the same can be a result of a genetranslocation of one PDGFRβ gene with another non-PDGFRβ gene.

Non-limiting examples of a PDGFRβ inhibitor include amuvatinib (MP470);axitinib (Inlyta®); imatinib (Gleevec®); masitinib; motesanibdiphosphate (AMG706, CAS 857876-30-3,N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide);nintedanib (BIBF1120, CAS 928326-83-4); pazopanib; quizartinib (AC220,CAS 950769-58-1); sorafenib (Nexavar®); sunitinib; telatinib(BAY57-9352, CAS 332012-40-5); and vatalanib (PTK787, CAS 212141-51-0).Additional examples of a PDGFRβ inhibitor are known in the art.

The phrase “dysregulation of a PI3K gene, a PI3K protein, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a chromosomal translocation that results in theexpression of a fusion protein including a PI3K kinase domain and afusion partner, a mutation in a PI3K gene that results in the expressiona PI3K protein that includes a deletion of at least one amino acid ascompared to a wildtype PI3K protein, a mutation in a PI3K gene thatresults in the expression of a PI3K protein with one or more pointmutations as compared to a wildtype PI3K protein, a mutation in a PI3Kgene that results in the expression of a PI3K protein with at least oneinserted amino acid as compared to a wildtype PI3K protein, a geneduplication that results in an increased level of PI3K protein in acell, or a mutation in a regulatory sequence (e.g., a promoter and/orenhancer) that results in an increased level of PI3K protein in a cell),an alternative spliced version of a PI3K mRNA that results in a PI3Kprotein having a deletion of at least one amino acid in the PI3K proteinas compared to the wild-type PI3K protein), or increased expression(e.g., increased levels) of a wildtype PI3K protein in a mammalian celldue to aberrant cell signaling and/or dysregulated autocrine/paracrinesignaling (e.g., as compared to a control non-cancerous cell). Asanother example, a dysregulation of a PI3K gene, a PI3K protein, orexpression or activity, or level of any of the same, can be a mutationin a PI3K gene that encodes a PI3K protein that is constitutively activeor has increased activity as compared to a protein encoded by a PI3Kgene that does not include the mutation. For example, a dysregulation ofa PI3K gene, a PI3K protein, or expression or activity, or level of anyof the same, can be the result of a gene or chromosome translocationwhich results in the expression of a fusion protein that contains afirst portion of a PI3K protein that includes a functional kinasedomain, and a second portion of a partner protein (i.e., that is notPI3K). In some examples, dysregulation of a PI3K gene, a PI3K protein,or expression or activity or level of any of the same can be a result ofa gene translocation of one PI3K gene with another non-PI3K gene.

Non-limiting examples of a PI3K inhibitor include 3-methyladenine; A66;alpelisib (BYL719); AMG319; AMG511; apitolisib (GDC-0980, RG7422);AS-252424; AS-604850; AS-605240; ASN003; AZD6482 (KIN-193); AZD8186;AZD8835; BGT226 (NVP-BGT226); buparlisib (BKM120); CAY10505; CH5132799;copanlisib (BAY 80-6946); CUDC-907; CZC24832; dactolisib (BEZ235,NVP-BEZ235); DS7423; duvelisib (IPI-145, INK1197); GDC-0032; GDC-0077;GDC-0084 (RG7666); GDC-0326; gedatolisib (PF-05212384, PKI-5587);GM-604; GNE-317; GS-9820; GSK1059615; GSK2292767; GSK2636771; HS-173;IC-87114; idelalisib (CAL-101, GS-1101); IPI-145; IPI-3063; IPI-549;LY294002; LY3023414; nemiralisib (GSK2269557); omipalisib (GSK2126458,GSK458); PF-04691502; PF-4989216; PI-103; PI-3065; pictilisib(GDC-0941); PIK-293; PIK-294; PIK-75; PIK-90; PIK-93; PIK-III;pilaralisib (XL147, SAR245408); PKI-402; PKI-587; PP-110; PQR309; PW-12;PX-866; quercetin; rigosertib; S14161; SAR245409 (XL765); SAR260301;SAR405; serabelisib (INK-1117, MLN-1117, TAK-1117); SF-1126; SF-2523;SN32976; sonolisib (PX-866); taselisib (GDC-0032); TB101110; TG100-115;TG100-713; TGR-1202; TGX-221; umbralisib (TGR-1202); voxtalisib (XL765,SAR245409); VPS34-IN1; VS-5584 (SB2343); WJD008; WX-037; wortmannin; andZSTK474. Additional examples of a PI3K inhibitor are known in the art.

The phrase “dysregulation of a RAF gene, a RAF protein, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a chromosomal translocation that results in theexpression of a fusion protein including a RAF kinase domain and afusion partner, a mutation in a RAF gene that results in the expressiona RAF protein that includes a deletion of at least one amino acid ascompared to a wildtype RAF protein, a mutation in a RAF gene thatresults in the expression of a RAF protein with one or more pointmutations as compared to a wildtype RAF protein, a mutation in a RAFgene that results in the expression of a RAF protein with at least oneinserted amino acid as compared to a wildtype RAF protein, a geneduplication that results in an increased level of RAF protein in a cell,or a mutation in a regulatory sequence (e.g., a promoter and/orenhancer) that results in an increased level of RAF protein in a cell),an alternative spliced version of a RAF mRNA that results in a RAFprotein having a deletion of at least one amino acid in the RAF proteinas compared to the wild-type RAF protein), or increased expression(e.g., increased levels) of a wildtype RAF protein in a mammalian celldue to aberrant cell signaling and/or dysregulated autocrine/paracrinesignaling (e.g., as compared to a control non-cancerous cell). Asanother example, a dysregulation of a RAF gene, a RAF protein, orexpression or activity, or level of any of the same, can be a mutationin a RAF gene that encodes a RAF protein that is constitutively activeor has increased activity as compared to a protein encoded by a RAF genethat does not include the mutation. For example, a dysregulation of aRAF gene, a RAF protein, or expression or activity, or level of any ofthe same, can be the result of a gene or chromosome translocation whichresults in the expression of a fusion protein that contains a firstportion of a RAF protein that includes a functional kinase domain, and asecond portion of a partner protein (i.e., that is not RAF). In someexamples, dysregulation of a RAF gene, a RAF protein, or expression oractivity or level of any of the same can be a result of a genetranslocation of one RAF gene with another non-RAF gene.

Non-limiting examples of a RAF inhibitor include((S)-2-{4-[3-(5-chloro-2-fluoro-3-methanesulfonylamino-phenyl)-1-isopropyl-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-1-methyl-ethyl)-carbamicacid methyl ester; ASN003; BMS-908662 (Bristol-Meyers Squibb, XL281);dabrafenib; GDC-0879; GSK2118436 (GlaxoSmithKline); LGX818 (Novartis);PLX3603 (Hofmann-LaRoche); PLX-4720; RAF265 (Novartis); R04987655;R05126766 (CH5127566); R05185426 (Hofmann-LaRoche); sorafenib(Nexavar®); and vemurafenib (RG7204, PLX4032). Additional examples of aRAF inhibitor are known in the art.

The phrase “dysregulation of a RAS gene, a RAS protein, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a chromosomal translocation that results in theexpression of a fusion protein including a RAS kinase domain and afusion partner, a mutation in a RAS gene that results in the expressiona RAS protein that includes a deletion of at least one amino acid ascompared to a wildtype RAS protein, a mutation in a RAS gene thatresults in the expression of a RAS protein with one or more pointmutations as compared to a wildtype RAS protein, a mutation in a RASgene that results in the expression of a RAS protein with at least oneinserted amino acid as compared to a wildtype RAS protein, a geneduplication that results in an increased level of RAS protein in a cell,or a mutation in a regulatory sequence (e.g., a promoter and/orenhancer) that results in an increased level of RAS protein in a cell),an alternative spliced version of a RAS mRNA that results in a RASprotein having a deletion of at least one amino acid in the RAS proteinas compared to the wild-type RAS protein), or increased expression(e.g., increased levels) of a wildtype RAS protein in a mammalian celldue to aberrant cell signaling and/or dysregulated autocrine/paracrinesignaling (e.g., as compared to a control non-cancerous cell). Asanother example, a dysregulation of a RAS gene, a RAS protein, orexpression or activity, or level of any of the same, can be a mutationin a RAS gene that encodes a RAS protein that is constitutively activeor has increased activity as compared to a protein encoded by a RAS genethat does not include the mutation. For example, a dysregulation of aRAS gene, a RAS protein, or expression or activity, or level of any ofthe same, can be the result of a gene or chromosome translocation whichresults in the expression of a fusion protein that contains a firstportion of a RAS protein that includes a functional kinase domain, and asecond portion of a partner protein (i.e., that is not RAS). In someexamples, dysregulation of a RAS gene, a RAS protein, or expression oractivity or level of any of the same can be a result of a genetranslocation of one RAS gene with another non-RAS gene.

Non-limiting examples of a RAS inhibitor include 037S-0604; a covalentquinazoline-based switch II pocket (SIIP) compound; ARS-1620; AZD4785;Kobe0065; Kobe2602; and LP1. Additional examples of a RAS inhibitor areknown in the art.

The phrase “dysregulation of a RET gene, a RET protein, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a chromosomal translocation that results in theexpression of a fusion protein including a RET kinase domain and afusion partner, a mutation in a RET gene that results in the expressiona RET protein that includes a deletion of at least one amino acid ascompared to a wildtype RET protein, a mutation in a RET gene thatresults in the expression of a RET protein with one or more pointmutations as compared to a wildtype RET protein, a mutation in a RETgene that results in the expression of a RET protein with at least oneinserted amino acid as compared to a wildtype RET protein, a geneduplication that results in an increased level of RET protein in a cell,or a mutation in a regulatory sequence (e.g., a promoter and/orenhancer) that results in an increased level of RET protein in a cell),an alternative spliced version of a RET mRNA that results in a RETprotein having a deletion of at least one amino acid in the RET proteinas compared to the wild-type RET protein), or increased expression(e.g., increased levels) of a wildtype RET protein in a mammalian celldue to aberrant cell signaling and/or dysregulated autocrine/paracrinesignaling (e.g., as compared to a control non-cancerous cell). Asanother example, a dysregulation of a RET gene, a RET protein, orexpression or activity, or level of any of the same, can be a mutationin a RET gene that encodes a RET protein that is constitutively activeor has increased activity as compared to a protein encoded by a RET genethat does not include the mutation. For example, a dysregulation of aRET gene, a RET protein, or expression or activity, or level of any ofthe same, can be the result of a gene or chromosome translocation whichresults in the expression of a fusion protein that contains a firstportion of a RET protein that includes a functional kinase domain, and asecond portion of a partner protein (i.e., that is not RAF). In someexamples, dysregulation of a RET gene, a RET protein, or expression oractivity or level of any of the same can be a result of a genetranslocation of one RET gene with another non-RET gene.

Non-limiting examples of a RET inhibitor include alectinib(9-Ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-yl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile);amuvatinib (MP470, HPK56)(N-(1,3-benzodioxol-5-ylmethyl)-4-([1]benzofuro[3,2-d]pyrimidin-4-yl)piperazine-1-carbothioamide);apatinib (YN968D1) (N-[4-(1-cyanocyclopentyl)phenyl-2-(4-picolyl)amino-3-Nicotinamide methanesulphonate);cabozantinib (Cometriq XL-184)(N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide);dovitinib (TKI258; GFKI-258; CHIR-258)((3Z)-4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1,3-dihydrobenzimidazol-2-ylidene]quinolin-2-one);famitinib(5-[2-(diethylamino)ethyl]-2-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-3-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4-one);fedratinib (SAR302503, TG101348)(N-(2-Methyl-2-propanyl)-3-{[5-methyl-2-({4-[2-(1-pyrrolidinyl)ethoxy]phenyl}amino)-4-pyrimidinyl]amino}benzenesulfonamide);foretinib (XL880, EXEL-2880, GSK1363089, GSK089)(N1′-[3-fluoro-4-[[6-methoxy-7-(3-morpholinopropoxy)-4-quinolyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide);fostamantinib (R788) (2H-Pyrido[3,2-b]-1,4-oxazin-3(4H)-one,6-[[5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl]amino]-2,2-dimethyl-4-[(phosphonooxy)methyl]-,sodium salt (1:2)); ilorasertib (ABT-348)(1-(4-(4-amino-7-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea);lenvatinib (E7080, Lenvima)(4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide);motesanib (AMG 706)(N-(3,3-Dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(pyridin-4-ylmethyl)amino]pyridine-3-carboxamide);nintedanib(3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methyoxycarbonyi-2-indolinone);ponatinib (AP24534)(3-(2-lmidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifiuoromethyl)phenyl]benzamide);PP242 (a TORKinib)(2-[4-Amino-1-(1-methylethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-1H-indol-5-ol);quizartinib(1-(5-(tert-Butyl)isoxazol-3-yl)-3-(4-(7-(2-morpholinoethoxy)benzo[d]imidazo[2,1-b]thiazol-2-yl)phenyl)urea);regorafenib (BAY 73-4506, stivarga)(4-[4-({[4-Chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamidehydrate); RXDX-105 (CEP-32496, agerafenib)(1-(3-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea);semaxanib (SU5416)((3Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-1,3-dihydro-2H-indol-2-one);sitravatinib (MGCD516, MG516)(N-(3-Fluoro-4-{[2-(5-{[(2-methoxyethyl)amino]methyl}-2-pyridinyl)thieno[3,2-b]pyridin-7-yl]oxy}phenyl)-N?-(4-fluorophenyl)-1,1-cyclopropanedicarboxamide);sorafenib (BAY 43-9006)(4-[4-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2-pyridinecarboxamide);vandetanib(N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine);vatalanib (PTK787, PTK/ZK, ZK222584)(N-(4-chlorophenyl)-4-(pyridin-4-ylmethyl)phthalazin-1-amine); AD-57(N-[4-[4-amino-1-(1-methylethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]-N′-[3-(trifiuoromethyl)phenyl]-urea);AD-80(1-[4-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)phenyl]-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea);AD-81(1-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea);ALW-11-41-27(N-(5-((4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)-2-methylphenyl)-5-(thiophen-2-yl)nicotinamide);BPR1K871(1-(3-chlorophenyl)-3-(5-(2-((7-(3-(dimethylamino)propoxy)quinazolin-4-yl)amino)ethyl)thiazol-2-yl)urea);CLM3(1-phenethyl-N-(1-phenylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine);EBI-907(N-(2-chloro-3-(1-cyclopropyl-8-methoxy-3H-pyrazolo[3,4-c]isoquinolin-7-yl)-4-fluorophenyl)-3-fluoropropane-1-sulfonamide);NVP-AST-487(N-[4-[(4-ethyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-N′-[4-[[6-(methylamino)-4-pyrimidinyl]oxy]phenyl]-urea);NVP-BBT594 (BBT594)(5-((6-acetamidopyrimidin-4-yl)oxy)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)indoline-1-carboxamide);PD173955(6-(2,6-dichlorophenyl)-8-methyl-2-(3-methylsulfanylanilino)pyrido[2,3-d]pyrimidin-7-one);PP2(4-amino-5-(4-chlorophenyl)-7-(dimethylethyl)pyrazolo[3,4-d]pyrimidine);PZ-1(N-(5-(tert-butyl)isoxazol-3-yl)-2-(4-(5-(1-methyl-1H-pyrazol-4-yl)-1Hbenzo[d]imidazol-1-yl)phenyl)acetamide);RPI-1(1,3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl)methylene]-H-indol-2-one;(3E)-3-[(4-hydroxyphenyl)methylidene]-5,6-dimethoxy-1H-indol-2-one);SGI-7079(3-[2-[[3-fluoro-4-(4-methyH-piperazinyi)phenyl]amino]-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-benzeneacetonitrile);SPP86(1-Isopropyl-3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine);SU4984(4-[4-[(E)-(2-oxo-1H-indol-3-ylidene)methyl]phenyl]piperazine-1-carbaldehyde);sunitinib (SU11248)(N-(2-Diethylaminoethyl)-5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide);TG101209(N-tert-butyl-3-(5-methyl-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)benzenesulfonamide);Withaferin A((4β,5β,6β,22R)-4,27-Dihydroxy-5,6:22,26-diepoxyergosta-2,24-diene-1,26-dione);XL-999((Z)-5-((1-ethylpiperidin-4-yl)amino)-3-((3-fluorophenyl)(5-methyl-1H-imidazol-2-yl)methylene)indolin-2-one);BPRU373 (a 5-phenylthiazol-2-ylamine-pyriminide derivative); CG-806(CG′806); DCC-2157; GTX-186; HG-6-63-01((E)-3-(2-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)vinyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifiuoromethyl)phenyl)-4-methylbenzamide);SW-01 (Cyclobenzaprine hydrochloride); XMD15-44(N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methyl-3-(pyridin-3-ylethynyl)benzamide(generated from structure)); Y078-DM1 (an antibody drug conjugatecomposed of a RET antibody (Y078) linked to a derivative of thecytotoxic agent maytansine); Y078-DM4 (an antibody drug conjugatecomposed of a RET antibody (Y078) linked to a derivative of thecytotoxic agent maytansine); ITRI-305 (D0N5 TB, DIB003599); BLU-667(((1S,4R)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-1-carboxamide);BLU6864; DS-5010; GSK3179106; GSK3352589; NMS-E668; and TPX0046.Additional examples of a RET inhibitor are known in the art.

The phrase “dysregulation of a ROS1 gene, a ROS1 protein, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a chromosomal translocation that results in theexpression of a fusion protein including a ROS1 kinase domain and afusion partner, a mutation in a ROS1 gene that results in the expressiona ROS1 protein that includes a deletion of at least one amino acid ascompared to a wild type ROS1 protein, a mutation in a ROS1 gene thatresults in the expression of a ROS1 protein with one or more pointmutations as compared to a wildtype ROS1 protein, a mutation in a ROS1gene that results in the expression of a ROS1 protein with at least oneinserted amino acid as compared to a wildtype ROS1 protein, a geneduplication that results in an increased level of ROS1 protein in acell, or a mutation in a regulatory sequence (e.g., a promoter and/orenhancer) that results in an increased level of ROS1 protein in a cell),an alternative spliced version of a ROS1 mRNA that results in a ROS1protein having a deletion of at least one amino acid in the ROS1 proteinas compared to the wild-type ROS1 protein), or increased expression(e.g., increased levels) of a wildtype ROS1 protein in a mammalian celldue to aberrant cell signaling and/or dysregulated autocrine/paracrinesignaling (e.g., as compared to a control non-cancerous cell). Asanother example, a dysregulation of a ROS1 gene, a ROS1 protein, orexpression or activity, or level of any of the same, can be a mutationin a ROS1 gene that encodes a ROS1 protein that is constitutively activeor has increased activity as compared to a protein encoded by a ROS1gene that does not include the mutation. For example, a dysregulation ofa ROS1 gene, a ROS1 protein, or expression or activity, or level of anyof the same, can be the result of a gene or chromosome translocationwhich results in the expression of a fusion protein that contains afirst portion of a ROS1 protein that includes a functional kinasedomain, and a second portion of a partner protein (i.e., that is notROS1). In some examples, dysregulation of a ROS1 gene, a ROS1 protein,or expression or activity or level of any of the same can be a result ofa gene translocation of one ROS1 gene with another non-ROS1 gene.

Non-limiting examples of a ROS1 inhibitor include cabozantinib;certinib; crizotinib; DS-605; entrectinib (RXDX-101); loriatinib(PF-06463922); anTPX-0005. Additional examples of a ROS1 inhibitor areknown in the art.

The phrase “dysregulation of a trkA gene, a trkA protein, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a chromosomal translocation that results in theexpression of a fusion protein including a trkA kinase domain and afusion partner, a mutation in a trkA gene that results in the expressiona trkA protein that includes a deletion of at least one amino acid ascompared to a wildtype trkA protein, a mutation in a trkA gene thatresults in the expression of a trkA protein with one or more pointmutations as compared to a wildtype trkA protein, a mutation in a trkAgene that results in the expression of a trkA protein with at least oneinserted amino acid as compared to a wildtype trkA protein, a geneduplication that results in an increased level of trkA protein in acell, or a mutation in a regulatory sequence (e.g., a promoter and/orenhancer) that results in an increased level of trkA protein in a cell),an alternative spliced version of a trkA mRNA that results in a trkAprotein having a deletion of at least one amino acid in the trkA proteinas compared to the wild-type trkA protein), or increased expression(e.g., increased levels) of a wildtype trkA protein in a mammalian celldue to aberrant cell signaling and/or dysregulated autocrine/paracrinesignaling (e.g., as compared to a control non-cancerous cell). Asanother example, a dysregulation of a trkA gene, a trkA protein, orexpression or activity, or level of any of the same, can be a mutationin a trkA gene that encodes a trkA protein that is constitutively activeor has increased activity as compared to a protein encoded by a trkAgene that does not include the mutation. For example, a dysregulation ofa trkA gene, a trkA protein, or expression or activity, or level of anyof the same, can be the result of a gene or chromosome translocationwhich results in the expression of a fusion protein that contains afirst portion of a trkA protein that includes a functional kinasedomain, and a second portion of a partner protein (i.e., that is nottrkA). In some examples, dysregulation of a trkA gene, a trkA protein,or expression or activity or level of any of the same can be a result ofa gene translocation of one trkA gene with another non-trkA gene.

The phrase “dysregulation of a trkB gene, a trkB protein, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a chromosomal translocation that results in theexpression of a fusion protein including a trkB kinase domain and afusion partner, a mutation in a trkB gene that results in the expressiona trkB protein that includes a deletion of at least one amino acid ascompared to a wildtype trkB protein, a mutation in a trkB gene thatresults in the expression of a trkB protein with one or more pointmutations as compared to a wildtype trkB protein, a mutation in a trkBgene that results in the expression of a trkB protein with at least oneinserted amino acid as compared to a wildtype trkB protein, a geneduplication that results in an increased level of trkB protein in acell, or a mutation in a regulatory sequence (e.g., a promoter and/orenhancer) that results in an increased level of trkB protein in a cell),an alternative spliced version of a trkB mRNA that results in a trkBprotein having a deletion of at least one amino acid in the trkB proteinas compared to the wild-type trkB protein), or increased expression(e.g., increased levels) of a wildtype trkB protein in a mammalian celldue to aberrant cell signaling and/or dysregulated autocrine/paracrinesignaling (e.g., as compared to a control non-cancerous cell). Asanother example, a dysregulation of a trkB gene, a trkB protein, orexpression or activity, or level of any of the same, can be a mutationin a trkB gene that encodes a trkB protein that is constitutively activeor has increased activity as compared to a protein encoded by a trkBgene that does not include the mutation. For example, a dysregulation ofa trkB gene, a trkB protein, or expression or activity, or level of anyof the same, can be the result of a gene or chromosome translocationwhich results in the expression of a fusion protein that contains afirst portion of a trkB protein that includes a functional kinasedomain, and a second portion of a partner protein (i.e., that is nottrkB). In some examples, dysregulation of a trkB gene, a trkB protein,or expression or activity or level of any of the same can be a result ofa gene translocation of one trkB gene with another non-trkB gene.

The phrase “dysregulation of a trkC gene, a trkC protein, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a chromosomal translocation that results in theexpression of a fusion protein including a trkC kinase domain and afusion partner, a mutation in a trkC gene that results in the expressiona trkC protein that includes a deletion of at least one amino acid ascompared to a wildtype trkC protein, a mutation in a trkC gene thatresults in the expression of a trkC protein with one or more pointmutations as compared to a wildtype trkC protein, a mutation in a trkCgene that results in the expression of a trkC protein with at least oneinserted amino acid as compared to a wildtype trkC protein, a geneduplication that results in an increased level of trkC protein in acell, or a mutation in a regulatory sequence (e.g., a promoter and/orenhancer) that results in an increased level of trkC protein in a cell),an alternative spliced version of a trkC mRNA that results in a trkCprotein having a deletion of at least one amino acid in the trkC proteinas compared to the wild-type trkC protein), or increased expression(e.g., increased levels) of a wildtype trkC protein in a mammalian celldue to aberrant cell signaling and/or dysregulated autocrine/paracrinesignaling (e.g., as compared to a control non-cancerous cell). Asanother example, a dysregulation of a trkC gene, a trkC protein, orexpression or activity, or level of any of the same, can be a mutationin a trkC gene that encodes a trkC protein that is constitutively activeor has increased activity as compared to a protein encoded by a trkCgene that does not include the mutation. For example, a dysregulation ofa trkC gene, a trkC protein, or expression or activity, or level of anyof the same, can be the result of a gene or chromosome translocationwhich results in the expression of a fusion protein that contains afirst portion of a trkC protein that includes a functional kinasedomain, and a second portion of a partner protein (i.e., that is nottrkC). In some examples, dysregulation of a trkC gene, a trkC protein,or expression or activity or level of any of the same can be a result ofa gene translocation of one trkC gene with another non-trkC gene.

Non-limiting examples of Trk (e.g., trkA, trkB, or trkC) inhibitorsinclude1-((3S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-yl)urea;4-aminopyrazolylpyrimidines, e.g., AZ-23(((S)-5-chloro-N2-(1-(5-fluoropyridin-2-yl)ethyl)-N4-(5-isopropoxy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine));afatinib; AG-879((2E)-3-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-cyano-2-propenethioamide);altiratinib(N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide);AR-256; AR-618; AR-772; AR-786; AZ-23((S)-5-Chloro-N2-(1-(5-fluoropyridin-2-yl)ethyl)-N4-(5-isopropoxy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine);AZ623; AZ64; AZD6918; cabozantinib(N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide);crizotinib; dabrafenib; danusertib (PHA-739358); dovatinib(4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-onemono 2-hydroxypropanoate hydrate); DS-6051; entrectinib; erlotinib;gefitinib; GNF-5837; GNF-8625((R)-1-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-[2,4′-bipyridin]-2′-yl)piperidin-4-ol);Gö6976(5,6,7,13-tetrahydro-13-methyl-5-oxo-12H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-12-propanenitrile);GTx-186; GW441756((3Z)-3-[(1-methylindol-3-yl)methylidene]-1H-pyrrolo[3,2-b]pyridin-2-one);imatinib; K252a((9S-(9α,10β,12α))-2,3,9,10,11,12-hexahydro-10-hydroxy-10-(methoxycarbonyl)-9-methyl-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i][1,6]benzodiazocin-1-one);lapatinib; lestaurtinib((5S,6S,8R)-6-Hydroxy-6-(hydroxymethyl)-5-methyl-7,8,14,15-tetrahydro-5H-16-oxa-4b,8a,14-triaza-5,8-methanodibenzo[b,h]cycloocta[jkl]cyclopenta[e]-as-indacen-13(6H)-one);LOXO-101; MGCD516; milcidib (PHA-848125AC); nilotinib; ONO-5390556;pazopanib; PLX7486; regorafenib(4-[4-({[4-Chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamidehydrate); RXDX101; sitravatinib(N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide);sunitinib; TPX-0005; trastuzumab; TSR-011; and VM-902A. Other examplesof Trk inhibitors are known in the art.

The phrase “dysregulation of a VEGFR-1 gene, a VEGFR-1 protein, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a chromosomal translocation that results in theexpression of a fusion protein including a VEGFR-1 kinase domain and afusion partner, a mutation in a VEGFR-1 gene that results in theexpression a VEGFR-1 protein that includes a deletion of at least oneamino acid as compared to a wildtype VEGFR-1 protein, a mutation in aVEGFR-1 gene that results in the expression of a VEGFR-1 protein withone or more point mutations as compared to a wildtype VEGFR-1 protein, amutation in a VEGFR-1 gene that results in the expression of a VEGFR-1protein with at least one inserted amino acid as compared to a wildtypeVEGFR-1 protein, a gene duplication that results in an increased levelof VEGFR-1 protein in a cell, or a mutation in a regulatory sequence(e.g., a promoter and/or enhancer) that results in an increased level ofVEGFR-1 protein in a cell), an alternative spliced version of a VEGFR-1mRNA that results in a VEGFR-1 protein having a deletion of at least oneamino acid in the VEGFR-1 protein as compared to the wild-type VEGFR-1protein), or increased expression (e.g., increased levels) of a wildtypeVEGFR-1 protein in a mammalian cell due to aberrant cell signalingand/or dysregulated autocrine/paracrine signaling (e.g., as compared toa control non-cancerous cell). As another example, a dysregulation of aVEGFR-1 gene, a VEGFR-1 protein, or expression or activity, or level ofany of the same, can be a mutation in a VEGFR-1 gene that encodes aVEGFR-1 protein that is constitutively active or has increased activityas compared to a protein encoded by a VEGFR-1 gene that does not includethe mutation. For example, a dysregulation of a VEGFR-1 gene, a VEGFR-1protein, or expression or activity, or level of any of the same, can bethe result of a gene or chromosome translocation which results in theexpression of a fusion protein that contains a first portion of aVEGFR-1 protein that includes a functional kinase domain, and a secondportion of a partner protein (i.e., that is not VEGFR-1). In someexamples, dysregulation of a VEGFR-1 gene, a VEGFR-1 protein, orexpression or activity or level of any of the same can be a result of agene translocation of one VEGFR-1 gene with another non-VEGFR-1 gene.

Non-limiting examples of a VEGFR-1 inhibitor include BMS690514((3R,4R)-4-Amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)piperidin-3-ol);axitinib; motesanib (AMG706, CAS 857876-30-3,N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide);nintedanib (BIBF1120, CAS 928326-83-4); pazopanib; and vatalanib(PTK787, CAS 212141-51-0). Additional examples of a VEGFR-1 inhibitorare known in the art.

The phrase “dysregulation of a VEGFR-2 gene, a VEGFR-2 protein, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a chromosomal translocation that results in theexpression of a fusion protein including a VEGFR-2 kinase domain and afusion partner, a mutation in a VEGFR-2 gene that results in theexpression a VEGFR-2 protein that includes a deletion of at least oneamino acid as compared to a wildtype VEGFR-2 protein, a mutation in aVEGFR-2 gene that results in the expression of a VEGFR-2 protein withone or more point mutations as compared to a wildtype VEGFR-2 protein, amutation in a VEGFR-2 gene that results in the expression of a VEGFR-2protein with at least one inserted amino acid as compared to a wildtypeVEGFR-2 protein, a gene duplication that results in an increased levelof VEGFR-2 protein in a cell, or a mutation in a regulatory sequence(e.g., a promoter and/or enhancer) that results in an increased level ofVEGFR-2 protein in a cell), an alternative spliced version of a VEGFR-2mRNA that results in a VEGFR-2 protein having a deletion of at least oneamino acid in the VEGFR-2 protein as compared to the wild-type VEGFR-2protein), or increased expression (e.g., increased levels) of a wildtypeVEGFR-2 protein in a mammalian cell due to aberrant cell signalingand/or dysregulated autocrine/paracrine signaling (e.g., as compared toa control non-cancerous cell). As another example, a dysregulation of aVEGFR-2 gene, a VEGFR-2 protein, or expression or activity, or level ofany of the same, can be a mutation in a VEGFR-2 gene that encodes aVEGFR-2 protein that is constitutively active or has increased activityas compared to a protein encoded by a VEGFR-2 gene that does not includethe mutation. For example, a dysregulation of a VEGFR-2 gene, a VEGFR-2protein, or expression or activity, or level of any of the same, can bethe result of a gene or chromosome translocation which results in theexpression of a fusion protein that contains a first portion of aVEGFR-2 protein that includes a functional kinase domain, and a secondportion of a partner protein (i.e., that is not VEGFR-2). In someexamples, dysregulation of a VEGFR-2 gene, a VEGFR-2 protein, orexpression or activity or level of any of the same can be a result of agene translocation of one VEGFR-2 gene with another non-VEGFR-2 gene.

Non-limiting examples of a VEGFR-2 inhibitor include BMS690514((3R,4R)-4-Amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)piperidin-3-ol);hypothemycin; glesatinib (MGCD265); sitravatinib (MGCD-516); axitinib;telatinib (BAY57-9352, CAS 332012-40-5); motesanib (AMG706, CAS857876-30-3,N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide);nintedanib (BIBF1120, CAS 928326-83-4); pazopanib; sorafenib (Nexavar®);and vatalanib (PTK787, CAS 212141-51-0). Additional examples of aVEGFR-2 inhibitor are known in the art.

The phrase “dysregulation of a VEGFR-3 gene, a VEGFR-3 protein, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a chromosomal translocation that results in theexpression of a fusion protein including a VEGFR-3 kinase domain and afusion partner, a mutation in a VEGFR-3 gene that results in theexpression a VEGFR-3 protein that includes a deletion of at least oneamino acid as compared to a wildtype VEGFR-3 protein, a mutation in aVEGFR-3 gene that results in the expression of a VEGFR-3 protein withone or more point mutations as compared to a wildtype VEGFR-3 protein, amutation in a VEGFR-3 gene that results in the expression of a VEGFR-3protein with at least one inserted amino acid as compared to a wildtypeVEGFR-3 protein, a gene duplication that results in an increased levelof VEGFR-3 protein in a cell, or a mutation in a regulatory sequence(e.g., a promoter and/or enhancer) that results in an increased level ofVEGFR-3 protein in a cell), an alternative spliced version of a VEGFR-3mRNA that results in a VEGFR-3 protein having a deletion of at least oneamino acid in the VEGFR-3 protein as compared to the wild-type VEGFR-3protein), or increased expression (e.g., increased levels) of a wildtypeVEGFR-3 protein in a mammalian cell due to aberrant cell signalingand/or dysregulated autocrine/paracrine signaling (e.g., as compared toa control non-cancerous cell). As another example, a dysregulation of aVEGFR-3 gene, a VEGFR-3 protein, or expression or activity, or level ofany of the same, can be a mutation in a VEGFR-3 gene that encodes aVEGFR-3 protein that is constitutively active or has increased activityas compared to a protein encoded by a VEGFR-3 gene that does not includethe mutation. For example, a dysregulation of a VEGFR-3 gene, a VEGFR-3protein, or expression or activity, or level of any of the same, can bethe result of a gene or chromosome translocation which results in theexpression of a fusion protein that contains a first portion of aVEGFR-3 protein that includes a functional kinase domain, and a secondportion of a partner protein (i.e., that is not VEGFR-3). In someexamples, dysregulation of a VEGFR-3 gene, a VEGFR-3 protein, orexpression or activity or level of any of the same can be a result of agene translocation of one VEGFR-3 gene with another non-VEGFR-3 gene.

Non-limiting examples of a VEGFR-3 inhibitor include BMS690514((3R,4R)-4-Amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)piperidin-3-ol);sitravatinib (MGCD-516); axitinib; telatinib (BAY57-9352, CAS332012-40-5); motesanib (AMG706, CAS 857876-30-3,N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide);nintedanib (BIBF1120, CAS 928326-83-4); pazopanib; and vatalanib(PTK787, CAS 212141-51-0). Additional examples of a VEGFR-3 inhibitorare known in the art.

Non-limiting examples of VEGFR (e.g., VEGFR-1, VEGFR-2, or VEGFR-3)include apatinib (YN968D1, CAS 811803-05-1); Aflibercept (Eylea®);axitinib; Bevacizumab; BHG712(4-Methyl-3-[[l-methyl-6-(3-pyridinyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]amino]-N-[3-(trifluoromethyl)phenyl]-benzamide,CAS 940310-85-0); BMS38703(N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide,CAS 345627-80-7); BMS690514((3R,4R)-4-Amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)piperidin-3-ol);brivanib (BMS-540215, CAS 649735-46-6); cabozantinib (XL184, CAS849217-68-1); cediranib (AZD2171, CAS 288383-20-1); foretinib(GSK1363089); fovitinib dilactic acid (TKI258, CAS 852433-84-2);glesatinib (MGCD265); hypothemycin; imatinib (Gleevec®); lenvatinib;lestaurtinib (CAS 111358-88-4); linfanib (ABT869, CAS 796967-16-3);Linifanib (ABT-869); motesanib (AMG706, CAS 857876-30-3,N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide);nintedanib (BIBF1120, CAS 928326-83-4); pazopanib; ponatinib (AP24534,CAS 943319-70-8); regorafenib (BAY73-4506, CAS 755037-03-7); Semaxinib(SU5416); sitravatinib (MGCD-516); sorafenib (Nexavar®); sunitinib;telatinib (BAY57-9352, CAS 332012-40-5); tesevatinib(N-(3,4-Dichloro-2-fluorophenyl)-6-methoxy-7-[[(3aα,5β,6aα)-octahydro-2-methylcyclopenta[c]pyrrol-5-yl]methoxy]-4-quinazolinamine,XL647, CAS 781613-23-8); tivozanib (AV951, CAS 475108-18-0); vandetanib;and vatalanib (PTK787, CAS 212141-51-0). Other examples of a VEGFRinhibitor are known in the art.

The phrase “dysregulation of a aromatase gene, an aromatase protein, orthe expression or activity or level of any of the same” refers to agenetic mutation (e.g., a mutation in an aromatase gene that results inthe expression an aromatase protein that includes a deletion of at leastone amino acid as compared to a wildtype aromatase protein, a mutationin an aromatase gene that results in the expression of an aromataseprotein with one or more point mutations as compared to a wildtypearomatase protein, a mutation in an aromatase gene that results in theexpression of an aromatase protein with at least one inserted amino acidas compared to a wildtype aromatase protein, a gene duplication thatresults in an increased level of aromatase protein in a cell, or amutation in a regulatory sequence (e.g., a promoter and/or enhancer)that results in an increased level of aromatase protein in a cell), analternative spliced version of an aromatase mRNA that results in anaromatase protein having a deletion of at least one amino acid in thearomatase protein as compared to the wild-type aromatase protein), orincreased expression (e.g., increased levels) of a wildtype aromatase ina mammalian cell due to aberrant cell signaling and/or dysregulatedautocrine/paracrine signaling (e.g., as compared to a controlnon-cancerous cell). As another example, a dysregulation of an aromatasegene, an aromatase protein, or expression or activity, or level of anyof the same, can be a mutation in an aromatase gene that encodes anaromatase protein that is constitutively active or has increasedactivity as compared to a protein encoded by an aromatase gene that doesnot include the mutation.

Non-limiting examples of an aromatase inhibitor includeaminoglutethimide, Arimidex (anastrozole), Aromasin (exemestane), Femara(letrozole), Teslac (testolactone), formestane, and vorozole. Additionalexamples of an aromatase inhibitor are known in the art.

The phrase “dysregulation of a EHMT2 gene, an EHMT2 protein, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a mutation in an EHMT2 gene that results in theexpression an EHMT2 protein that includes a deletion of at least oneamino acid as compared to a wildtype EHMT2 protein, a mutation in anEHMT2 gene that results in the expression of an EHMT2 protein with oneor more point mutations as compared to a wildtype EHMT2 protein, amutation in an EHMT2 gene that results in the expression of an EHMT2protein with at least one inserted amino acid as compared to a wildtypeEHMT2 protein, a gene duplication that results in an increased level ofEHMT2 protein in a cell, or a mutation in a regulatory sequence (e.g., apromoter and/or enhancer) that results in an increased level of EHMT2protein in a cell), an alternative spliced version of an EHMT2 mRNA thatresults in an EHMT2 protein having a deletion of at least one amino acidin the EHMT2 protein as compared to the wild-type EHMT2 protein), orincreased expression (e.g., increased levels) of a wildtype EHMT2 in amammalian cell due to aberrant cell signaling and/or dysregulatedautocrine/paracrine signaling (e.g., as compared to a controlnon-cancerous cell). As another example, a dysregulation of an EHMT2gene, an EHMT2 protein, or expression or activity, or level of any ofthe same, can be a mutation in an EHMT2 gene that encodes an EHMT2protein that is constitutively active or has increased activity ascompared to a protein encoded by an EHMT2 gene that does not include themutation.

Non-limiting examples of an EHMT2 inhibitor include2-(4,4-difluoropiperidin-1-yl)-N-(1-isopropylpiperidin-4-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine;2-(4-isopropyl-1,4-diazepan-1-yl)-N-(1-isopropylpiperidin-4-yl)-6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinazolin-4-amine;A-366; BIX-01294 (BIX); BIX-01338; BRD4770; DCG066; EZM8266;N-(1-isopropylpiperidin-4-yl)-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-7-(3-(piperidin-1-yl)propoxy)quinazolin-4-amine;UNC0224; UNC0321; UNC0631; UNC0638(2-cyclohexyl-6-methoxy-N-[1-(1-methylethyl)-4-piperidinyl]-7-[3-(1-pyrrolidinyl)propoxy]-4-quinazolinamine);UNC0642(2-(4,4-Difluoro-1-piperidinyl)-6-methoxy-N-[1-(1-methylethyl)-4-piperidinyl]-7-[3-(1-pyrrolidinyl)propoxy]-4-quinazolinamine);and UNC0646. Additional examples of an EHMT2 inhibitor are known in theart.

The phrase “dysregulation of a RAC1 gene, an RAC1 protein, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a mutation in an RAC1 gene that results in theexpression an RAC1 protein that includes a deletion of at least oneamino acid as compared to a wildtype RAC1 protein, a mutation in an RAC1gene that results in the expression of an RAC1 protein with one or morepoint mutations as compared to a wildtype RAC1 protein, a mutation in anRAC1 gene that results in the expression of an RAC1 protein with atleast one inserted amino acid as compared to a wildtype RAC1 protein, agene duplication that results in an increased level of RAC1 protein in acell, or a mutation in a regulatory sequence (e.g., a promoter and/orenhancer) that results in an increased level of RAC1 protein in a cell),an alternative spliced version of an RAC1 mRNA that results in an RAC1protein having a deletion of at least one amino acid in the RAC1 proteinas compared to the wild-type RAC1 protein), or increased expression(e.g., increased levels) of a wildtype RAC1 in a mammalian cell due toaberrant cell signaling and/or dysregulated autocrine/paracrinesignaling (e.g., as compared to a control non-cancerous cell). Asanother example, a dysregulation of an RAC1 gene, an RAC1 protein, orexpression or activity, or level of any of the same, can be a mutationin an RAC1 gene that encodes an RAC1 protein that is constitutivelyactive or has increased activity as compared to a protein encoded by anRAC1 gene that does not include the mutation.

Non-limiting examples of an RAC1 inhibitor include azathioprine;EHop-016; EHT1864; and NSC23766. Additional examples of an RAC1inhibitor are known in the art.

The phrase “dysregulation of a SOS1 gene, an SOS1 protein, or theexpression or activity or level of any of the same” refers to a geneticmutation (e.g., a mutation in an SOS1 gene that results in theexpression an SOS1 protein that includes a deletion of at least oneamino acid as compared to a wildtype SOS1 protein, a mutation in an SOS1gene that results in the expression of an SOS1 protein with one or morepoint mutations as compared to a wildtype SOS1 protein, a mutation in anSOS1 gene that results in the expression of an SOS1 protein with atleast one inserted amino acid as compared to a wildtype SOS1 protein, agene duplication that results in an increased level of SOS1 protein in acell, or a mutation in a regulatory sequence (e.g., a promoter and/orenhancer) that results in an increased level of SOS1 protein in a cell),an alternative spliced version of an SOS1 mRNA that results in an SOS1protein having a deletion of at least one amino acid in the SOS1 proteinas compared to the wild-type SOS1 protein), or increased expression(e.g., increased levels) of a wildtype SOS1 in a mammalian cell due toaberrant cell signaling and/or dysregulated autocrine/paracrinesignaling (e.g., as compared to a control non-cancerous cell). Asanother example, a dysregulation of an SOS1 gene, an SOS1 protein, orexpression or activity, or level of any of the same, can be a mutationin an SOS1 gene that encodes an SOS1 protein that is constitutivelyactive or has increased activity as compared to a protein encoded by anSOS1 gene that does not include the mutation.

Non-limiting examples of an SOS1 inhibitor are described in PCTPublication No. 2018/115380, incorporated herein by reference.Additional examples of an SOS1 inhibitor are known in the art.

Non-limiting examples of multi-kinase inhibitors (MKIs) includedasatinib and sunitinib.

In some embodiments, the treatment period is at least 7 days (e.g., atleast or about 8 days, at least or about 9 days, at least or about 10days, at least or about 11 days, at least or about 12 days, at least orabout 13 days, at least or about 14 days, at least or about 15 days, atleast or about 16 days, at least or about 17 days, at least or about 18days, at least or about 19 days, at least or about 20 days, at least orabout 21 days, at least or about 22 days, at least or about 23 days, atleast or about 24 days, at least or about 25 days, at least or about 26days, at least or about 27 days, at least or about 28 days, at least orabout 29 days, or at least or about 30 days), the FGFR inhibitor isJNJ-42756493, and a daily dose of about 6 mg to about 12 mg (e.g., about6 mg to about 11 mg, about 10 mg, about 9 mg, about 8 mg, or about 7 mg;about 7 mg to about 12 mg, about 11 mg, about 10 mg, about 9 mg, orabout 8 mg; about 8 mg to about 12 mg, about 11 mg, about 10 mg, orabout 9 mg; about 9 mg to about 12 mg, about 11 mg, or about 10 mg;about 10 mg to about 12 mg or about 11 mg; or about 11 mg to about 12mg) of the first FGFR inhibitor is administered to the patient over thetreatment period.

In some embodiments, the treatment period is at least 21 days (e.g., atleast or about 22 days, at least or about 23 days, at least or about 24days, at least or about 25 days, at least or about 26 days, at least orabout 27 days, at least or about 28 days, at least or about 29 days, atleast or about 30 days, at least or about 31 days, at least or about 32days, at least or about 33 days, at least or about 34 days, at least orabout 35 days, at least or about 36 days, at least or about 37 days, atleast or about 38 days, at least or about 39 days, or at least or about40 days) the first FGFR is BGJ398, and a daily dose of about 50 mg toabout 125 mg (e.g., about 50 mg to about 120 mg, about 115 mg, about 110mg, about 105 mg, about 100 mg, about 95 mg, about 90 mg, about 85 mg,about 80 mg, about 75 mg, about 70 mg, about 65 mg, about 60 mg, orabout 55 mg; about 55 mg to about 120 mg, about 115 mg, about 110 mg,about 105 mg, about 100 mg, about 95 mg, about 90 mg, about 85 mg, about80 mg, about 75 mg, about 70 mg, about 65 mg, or about 60 mg; about 60mg to about 120 mg, about 115 mg, about 110 mg, about 105 mg, about 100mg, about 95 mg, about 90 mg, about 85 mg, about 80 mg, about 75 mg,about 70 mg, or about 65 mg; about 65 mg to about 120 mg, about 115 mg,about 110 mg, about 105 mg, about 100 mg, about 95 mg, about 90 mg,about 85 mg, about 80 mg, about 75 mg, or about 70 mg; about 70 mg toabout 120 mg, about 115 mg, about 110 mg, about 105 mg, about 100 mg,about 95 mg, about 90 mg, about 85 mg, about 80 mg, or about 75 mg;about 75 mg to about 120 mg, about 115 mg, about 110 mg, about 105 mg,about 100 mg, about 95 mg, about 90 mg, about 85 mg, or about 80 mg;about 80 mg to about 120 mg, about 115 mg, about 110 mg, about 105 mg,about 100 mg, about 95 mg, about 90 mg, or about 85 mg; about 85 mg toabout 120 mg, about 115 mg, about 110 mg, about 105 mg, about 100 mg,about 95 mg, or about 90 mg; about 90 mg to about 120 mg, about 115 mg,about 110 mg, about 105 mg, about 100 mg, or about 95 mg; about 95 mg toabout 120 mg, about 115 mg, about 110 mg, about 105 mg, or about 100 mg;about 100 mg to about 120 mg, about 115 mg, about 110 mg, or about 105mg; about 105 mg to about 120 mg, about 115 mg, or about 110 mg; about110 mg to about 120 mg or about 115 mg; or about 115 mg to about 120 mg)of the first FGFR inhibitor is administered to the patient over thetreatment period.

Also provided are methods of treating a FGFR-associated cancer in apatient, which include: (a) administering to a patient identified ordiagnosed as having an FGFR-associated cancer one or more doses of afirst FGFR inhibitor over a treatment period; (b) determining the levelof phosphate in a biological sample comprising blood, serum, or plasmaobtained from the patient after the treatment period; (c) selecting apatient having an elevated level of phosphate in the biological sampleas compared to a reference level of phosphate; and (d) ceasingadministration of the first FGFR inhibitor and initiating administrationof a therapeutically effective amount of a compound as described hereinor a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition containing the same, to the selected patient.In certain embodiments, the treatment period is at least 7 days. Inother embodiments, the treatment period is at least 21 days. In certainembodiments, the first FGFR inhibitor is JNJ-42756493 or BGJ398. By wayof example, the first FGFR inhibitor can be JNJ-42756493 and a dailydose of 6 mg to 12 mg of the first FGFR inhibitor is administered to thepatient over the treatment period (e.g., 7 days). As another example,the first FGFR inhibitor can be BGJ398 and a daily dose of 50 mg to 125mg of the first FGFR inhibitor is administered to the patient over thetreatment period (e.g., 21 days). In certain embodiments, the patient isadministered a therapeutically effective amount of a phosphate binderover the treatment period. In certain embodiments, step (d) furthercomprises ceasing administration of the phosphate binder to the selectedpatient. In certain embodiments, step (d) further includes administeringa decreased dose of the phosphate binder to the selected patientrelative to the dose of the phosphate binder administered to the patientover the treatment period. JNJ-42756493 (erdafitinib) is also known asJNJ-493 and has the following systematic name,N1-(3,5-dimethoxyphenyl)-N2-isopropyl-N1-(3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl)ethane-1,2-diamine,and the following structure:

BGJ398 (infigratinib) has the following systematic name,3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(6-((4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-1-methylurea,and the following chemical structure:

Also provided are methods of increasing the time of remission of aFGFR-associated cancer in a patient that include (a) selecting,identifying, or diagnosing a patient as having a FGFR-associated cancer(e.g., any of the FGFR-associated cancers described herein), and (b)administering a therapeutically effective amount of a compound ofFormula I (e.g., any of the exemplary compounds described herein), or apharmaceutically acceptable salt or solvate thereof. Also provided aremethods of increasing the time of remission of a FGFR-associated cancerin a patient that include administering a therapeutically effectiveamount of a compound of Formula I (e.g., any of the exemplary compoundsdescribed herein), or a pharmaceutically acceptable salt or solvatethereof to a patient having a FGFR-associated cancer (e.g., any of theexemplary FGFR-associated cancers described herein).

In some examples of any of the methods of increasing the time ofremission of a FGFR-associated cancer in a patient, the increase in thetime of remission is compared to a control patient (e.g., a patient or apopulation of patients having the same or a similar type ofFGFR-associated cancer). In some examples, the patient is not yet inremission. In other examples, the patient is already in remission. Insome examples, the increase in remission is a statistically significantincrease. In some examples, the increase in the time of remission isabout 1 day to about 10 years, about 9.5 years, about 9 years, about 8.5years, about 8 years, about 7.5 years, about 7 years, about 6.5 years,about 6 years, about 5.5 years, about 5 years, about 4.5 years, about 4years, about 3.5 years, about 3 years, about 2.5 years, about 2 years,about 1.5 years, about 1 year, about 10 months, about 8 months, about 6months, about 4 months, about 2 months, about 1 month, or about 2 weeks;about 2 weeks to about 10 years, about 9.5 years, about 9 years, about8.5 years, about 8 years, about 7.5 years, about 7 years, about 6.5years, about 6 years, about 5.5 years, about 5 years, about 4.5 years,about 4 years, about 3.5 years, about 3 years, about 2.5 years, about 2years, about 1.5 years, about 1 year, about 10 months, about 8 months,about 6 months, about 4 months, about 2 months, or about 1 month; about1 month to about 10 years, about 9.5 years, about 9 years, about 8.5years, about 8 years, about 7.5 years, about 7 years, about 6.5 years,about 6 years, about 5.5 years, about 5 years, about 4.5 years, about 4years, about 3.5 years, about 3 years, about 2.5 years, about 2 years,about 1.5 years, about 1 year, about 10 months, about 8 months, about 6months, about 4 months, or about 2 months; about 2 month to about 10years, about 9.5 years, about 9 years, about 8.5 years, about 8 years,about 7.5 years, about 7 years, about 6.5 years, about 6 years, about5.5 years, about 5 years, about 4.5 years, about 4 years, about 3.5years, about 3 years, about 2.5 years, about 2 years, about 1.5 years,about 1 year, about 10 months, about 8 months, about 6 months, or about4 months; about 4 month to about 10 years, about 9.5 years, about 9years, about 8.5 years, about 8 years, about 7.5 years, about 7 years,about 6.5 years, about 6 years, about 5.5 years, about 5 years, about4.5 years, about 4 years, about 3.5 years, about 3 years, about 2.5years, about 2 years, about 1.5 years, about 1 year, about 10 months,about 8 months, or about 6 months; about 6 month to about 10 years,about 9.5 years, about 9 years, about 8.5 years, about 8 years, about7.5 years, about 7 years, about 6.5 years, about 6 years, about 5.5years, about 5 years, about 4.5 years, about 4 years, about 3.5 years,about 3 years, about 2.5 years, about 2 years, about 1.5 years, about 1year, about 10 months, or about 8 months; about 8 month to about 10years, about 9.5 years, about 9 years, about 8.5 years, about 8 years,about 7.5 years, about 7 years, about 6.5 years, about 6 years, about5.5 years, about 5 years, about 4.5 years, about 4 years, about 3.5years, about 3 years, about 2.5 years, about 2 years, about 1.5 years,about 1 year, or about 10 months; about 10 month to about 10 years,about 9.5 years, about 9 years, about 8.5 years, about 8 years, about7.5 years, about 7 years, about 6.5 years, about 6 years, about 5.5years, about 5 years, about 4.5 years, about 4 years, about 3.5 years,about 3 years, about 2.5 years, about 2 years, about 1.5 years, or about1 year; about 1 year to about 10 years, about 9.5 years, about 9 years,about 8.5 years, about 8 years, about 7.5 years, about 7 years, about6.5 years, about 6 years, about 5.5 years, about 5 years, about 4.5years, about 4 years, about 3.5 years, about 3 years, about 2.5 years,about 2 years, or about 1.5 years; about 1.5 years to about 10 years,about 9.5 years, about 9 years, about 8.5 years, about 8 years, about7.5 years, about 7 years, about 6.5 years, about 6 years, about 5.5years, about 5 years, about 4.5 years, about 4 years, about 3.5 years,about 3 years, about 2.5 years, to about 2 years; about 2 years to about10 years, about 9.5 years, about 9 years, about 8.5 years, about 8years, about 7.5 years, about 7 years, about 6.5 years, about 6 years,about 5.5 years, about 5 years, about 4.5 years, about 4 years, about3.5 years, about 3 years, or about 2.5 years; about 2.5 years to about10 years, about 9.5 years, about 9 years, about 8.5 years, about 8years, about 7.5 years, about 7 years, about 6.5 years, about 6 years,about 5.5 years, about 5 years, about 4.5 years, about 4 years, about3.5 years, or about 3 years; about 3 years to about 10 years, about 9.5years, about 9 years, about 8.5 years, about 8 years, about 7.5 years,about 7 years, about 6.5 years, about 6 years, about 5.5 years, about 5years, about 4.5 years, about 4 years, or about 3.5 years; about 3.5years to about 10 years, about 9.5 years, about 9 years, about 8.5years, about 8 years, about 7.5 years, about 7 years, about 6.5 years,about 6 years, about 5.5 years, about 5 years, about 4.5 years, or about4 years; about 4 years to about 10 years, about 9.5 years, about 9years, about 8.5 years, about 8 years, about 7.5 years, about 7 years,about 6.5 years, about 6 years, about 5.5 years, about 5 years, or about4.5 years; about 4.5 years to about 10 years, about 9.5 years, about 9years, about 8.5 years, about 8 years, about 7.5 years, about 7 years,about 6.5 years, about 6 years, about 5.5 years, or about 5 years; about5 years to about 10 years, about 9.5 years, about 9 years, about 8.5years, about 8 years, about 7.5 years, about 7 years, about 6.5 years,about 6 years, or about 5.5 years; about 5.5 years to about 10 years,about 9.5 years, about 9 years, about 8.5 years, about 8 years, about7.5 years, about 7 years, about 6.5 years, or about 6 years; about 6years to about 10 years, about 9.5 years, about 9 years, about 8.5years, about 8 years, about 7.5 years, about 7 years, or about 6.5years; about 6.5 years to about 10 years, about 9.5 years, about 9years, about 8.5 years, about 8 years, about 7.5 years, or about 7years; about 7 years to about 10 years, about 9.5 years, about 9 years,about 8.5 years, about 8 years, or about 7.5 years; about 7.5 years toabout 10 years, about 9.5 years, about 9 years, about 8.5 years, orabout 8 years; about 8 years to about 10 years, about 9.5 years, about 9years, or about 8.5 years; about 8.5 years to about 10 years, about 9.5years, or about 9 years; about 9 years to about 10 years or about 9.5years; or about 9.5 years to about 10 years (e.g., compared to a controlpatient, e.g., a patient or a population of patients having the same ora similar type of FGFR-associated cancer).

Also provided is a compound of Formula I or pharmaceutically acceptablesalt or solvate thereof for use in increasing the time of remission of aFGFR-associated cancer in a patient. Also provided is the use of acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof in the manufacture of a medicament for increasing the time ofremission of a FGFR-associated cancer in a patient.

Methods for determining whether or not a patient is in remission areknown by those skilled in the art. For example, a PET scan, MRI, CTscan, ultrasound, and X-ray of the patient's body may be obtained, andsuch data can be used to determine whether or not a patient is inremission. In some examples, diagnostic tests can be performed onsamples from a patient (e.g., a blood sample or a biopsy) to determinewhether or not the patient is still in remission.

Also provided are methods of increasing the time of survival of apatient having a FGFR-associated cancer that include: selecting,diagnosing, or identifying a patient as having a FGFR-associated cancer;and administering to a subject selected, diagnosed, or identified ashaving a FGFR-associated cancer a therapeutically effective amount of acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof. Also provided are methods of increasing the time of survival ofa patient having a FGFR-associated cancer that include administering toa subject having a FGFR-associated cancer a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof. In some embodiments of any of the methods ofincreasing the time of survival of a subject having a FGFR-associatedcancer, the increase in the time of survival is compared to a controlpatient (e.g., a patient or a population of patients having the same ora similar type of FGFR-associated cancer). In some examples, the patientcan have an early stage of a FGFR-associated cancer (e.g., Stage 1 or2). In some embodiments, the patient can have a late stage of aFGFR-associated cancer (e.g., Stage 3 or 4). In some examples, theincrease in the time of survival is a statistically significantincrease. In some examples, the increase in the time of survival isabout 1 day to about 40 years, about 38 years, about 36 years, about 34years, about 32 years, about 30 years, about 28 years, about 26 years,about 24 years, about 22 years, about 20 years, about 18 years, about 16years, about 14 years, about 12 years, about 10 years, about 9.5 years,about 9 years, about 8.5 years, about 8 years, about 7.5 years, about 7years, about 6.5 years, about 6 years, about 5.5 years, about 5 years,about 4.5 years, about 4 years, about 3.5 years, about 3 years, about2.5 years, about 2 years, about 1.5 years, about 1 year, about 10months, about 8 months, about 6 months, about 4 months, about 2 months,about 1 month, or about 2 weeks; about 2 weeks to about 40 years, about38 years, about 36 years, about 34 years, about 32 years, about 30years, about 28 years, about 26 years, about 24 years, about 22 years,about 20 years, about 18 years, about 16 years, about 14 years, about 12years, about 10 years, about 9.5 years, about 9 years, about 8.5 years,about 8 years, about 7.5 years, about 7 years, about 6.5 years, about 6years, about 5.5 years, about 5 years, about 4.5 years, about 4 years,about 3.5 years, about 3 years, about 2.5 years, about 2 years, about1.5 years, about 1 year, about 10 months, about 8 months, about 6months, about 4 months, about 2 months, or about 1 month; about 1 monthto about 40 years, about 38 years, about 36 years, about 34 years, about32 years, about 30 years, about 28 years, about 26 years, about 24years, about 22 years, about 20 years, about 18 years, about 16 years,about 14 years, about 12 years, about 10 years, about 9.5 years, about 9years, about 8.5 years, about 8 years, about 7.5 years, about 7 years,about 6.5 years, about 6 years, about 5.5 years, about 5 years, about4.5 years, about 4 years, about 3.5 years, about 3 years, about 2.5years, about 2 years, about 1.5 years, about 1 year, about 10 months,about 8 months, about 6 months, about 4 months, or about 2 months; about2 months to about 40 years, about 38 years, about 36 years, about 34years, about 32 years, about 30 years, about 28 years, about 26 years,about 24 years, about 22 years, about 20 years, about 18 years, about 16years, about 14 years, about 12 years, about 10 years, about 9.5 years,about 9 years, about 8.5 years, about 8 years, about 7.5 years, about 7years, about 6.5 years, about 6 years, about 5.5 years, about 5 years,about 4.5 years, about 4 years, about 3.5 years, about 3 years, about2.5 years, about 2 years, about 1.5 years, about 1 year, about 10months, about 8 months, about 6 months, or about 4 months; about 4months to about 40 years, about 38 years, about 36 years, about 34years, about 32 years, about 30 years, about 28 years, about 26 years,about 24 years, about 22 years, about 20 years, about 18 years, about 16years, about 14 years, about 12 years, about 10 years, about 9.5 years,about 9 years, about 8.5 years, about 8 years, about 7.5 years, about 7years, about 6.5 years, about 6 years, about 5.5 years, about 5 years,about 4.5 years, about 4 years, about 3.5 years, about 3 years, about2.5 years, about 2 years, about 1.5 years, about 1 year, about 10months, about 8 months, or about 6 months; about 6 months to about 40years, about 38 years, about 36 years, about 34 years, about 32 years,about 30 years, about 28 years, about 26 years, about 24 years, about 22years, about 20 years, about 18 years, about 16 years, about 14 years,about 12 years, about 10 years, about 9.5 years, about 9 years, about8.5 years, about 8 years, about 7.5 years, about 7 years, about 6.5years, about 6 years, about 5.5 years, about 5 years, about 4.5 years,about 4 years, about 3.5 years, about 3 years, about 2.5 years, about 2years, about 1.5 years, about 1 year, about 10 months, or about 8months; about 8 months to about 40 years, about 38 years, about 36years, about 34 years, about 32 years, about 30 years, about 28 years,about 26 years, about 24 years, about 22 years, about 20 years, about 18years, about 16 years, about 14 years, about 12 years, about 10 years,about 9.5 years, about 9 years, about 8.5 years, about 8 years, about7.5 years, about 7 years, about 6.5 years, about 6 years, about 5.5years, about 5 years, about 4.5 years, about 4 years, about 3.5 years,about 3 years, about 2.5 years, about 2 years, about 1.5 years, about 1year, or about 10 months; about 10 months to about 40 years, about 38years, about 36 years, about 34 years, about 32 years, about 30 years,about 28 years, about 26 years, about 24 years, about 22 years, about 20years, about 18 years, about 16 years, about 14 years, about 12 years,about 10 years, about 9.5 years, about 9 years, about 8.5 years, about 8years, about 7.5 years, about 7 years, about 6.5 years, about 6 years,about 5.5 years, about 5 years, about 4.5 years, about 4 years, about3.5 years, about 3 years, about 2.5 years, about 2 years, about 1.5years, or about 1 year; about 1 year to about 40 years, about 38 years,about 36 years, about 34 years, about 32 years, about 30 years, about 28years, about 26 years, about 24 years, about 22 years, about 20 years,about 18 years, about 16 years, about 14 years, about 12 years, about 10years, about 9.5 years, about 9 years, about 8.5 years, about 8 years,about 7.5 years, about 7 years, about 6.5 years, about 6 years, about5.5 years, about 5 years, about 4.5 years, about 4 years, about 3.5years, about 3 years, about 2.5 years, about 2 years, or about 1.5years; about 1.5 year to about 40 years, about 38 years, about 36 years,about 34 years, about 32 years, about 30 years, about 28 years, about 26years, about 24 years, about 22 years, about 20 years, about 18 years,about 16 years, about 14 years, about 12 years, about 10 years, about9.5 years, about 9 years, about 8.5 years, about 8 years, about 7.5years, about 7 years, about 6.5 years, about 6 years, about 5.5 years,about 5 years, about 4.5 years, about 4 years, about 3.5 years, about 3years, about 2.5 years, or about 2 years; about 2 year to about 40years, about 38 years, about 36 years, about 34 years, about 32 years,about 30 years, about 28 years, about 26 years, about 24 years, about 22years, about 20 years, about 18 years, about 16 years, about 14 years,about 12 years, about 10 years, about 9.5 years, about 9 years, about8.5 years, about 8 years, about 7.5 years, about 7 years, about 6.5years, about 6 years, about 5.5 years, about 5 years, about 4.5 years,about 4 years, about 3.5 years, about 3 years, or about 2.5 years; about2.5 year to about 40 years, about 38 years, about 36 years, about 34years, about 32 years, about 30 years, about 28 years, about 26 years,about 24 years, about 22 years, about 20 years, about 18 years, about 16years, about 14 years, about 12 years, about 10 years, about 9.5 years,about 9 years, about 8.5 years, about 8 years, about 7.5 years, about 7years, about 6.5 years, about 6 years, about 5.5 years, about 5 years,about 4.5 years, about 4 years, about 3.5 years, or about 3 years; about3 year to about 40 years, about 38 years, about 36 years, about 34years, about 32 years, about 30 years, about 28 years, about 26 years,about 24 years, about 22 years, about 20 years, about 18 years, about 16years, about 14 years, about 12 years, about 10 years, about 9.5 years,about 9 years, about 8.5 years, about 8 years, about 7.5 years, about 7years, about 6.5 years, about 6 years, about 5.5 years, about 5 years,about 4.5 years, about 4 years, or about 3.5 years; about 3.5 years toabout 40 years, about 38 years, about 36 years, about 34 years, about 32years, about 30 years, about 28 years, about 26 years, about 24 years,about 22 years, about 20 years, about 18 years, about 16 years, about 14years, about 12 years, about 10 years, about 9.5 years, about 9 years,about 8.5 years, about 8 years, about 7.5 years, about 7 years, about6.5 years, about 6 years, about 5.5 years, about 5 years, about 4.5years, or about 4 years; about 4 years to about 40 years, about 38years, about 36 years, about 34 years, about 32 years, about 30 years,about 28 years, about 26 years, about 24 years, about 22 years, about 20years, about 18 years, about 16 years, about 14 years, about 12 years,about 10 years, about 9.5 years, about 9 years, about 8.5 years, about 8years, about 7.5 years, about 7 years, about 6.5 years, about 6 years,about 5.5 years, about 5 years, or about 4.5 years; about 4.5 years toabout 40 years, about 38 years, about 36 years, about 34 years, about 32years, about 30 years, about 28 years, about 26 years, about 24 years,about 22 years, about 20 years, about 18 years, about 16 years, about 14years, about 12 years, about 10 years, about 9.5 years, about 9 years,about 8.5 years, about 8 years, about 7.5 years, about 7 years, about6.5 years, about 6 years, about 5.5 years, or about 5 years; about 5years to about 40 years, about 38 years, about 36 years, about 34 years,about 32 years, about 30 years, about 28 years, about 26 years, about 24years, about 22 years, about 20 years, about 18 years, about 16 years,about 14 years, about 12 years, about 10 years, about 9.5 years, about 9years, about 8.5 years, about 8 years, about 7.5 years, about 7 years,about 6.5 years, about 6 years, or about 5.5 years; about 5.5 years toabout 40 years, about 38 years, about 36 years, about 34 years, about 32years, about 30 years, about 28 years, about 26 years, about 24 years,about 22 years, about 20 years, about 18 years, about 16 years, about 14years, about 12 years, about 10 years, about 9.5 years, about 9 years,about 8.5 years, about 8 years, about 7.5 years, about 7 years, about6.5 years, or about 6 years; about 6 years to about 40 years, about 38years, about 36 years, about 34 years, about 32 years, about 30 years,about 28 years, about 26 years, about 24 years, about 22 years, about 20years, about 18 years, about 16 years, about 14 years, about 12 years,about 10 years, about 9.5 years, about 9 years, about 8.5 years, about 8years, about 7.5 years, about 7 years, or about 6.5 years; about 6.5years to about 40 years, about 38 years, about 36 years, about 34 years,about 32 years, about 30 years, about 28 years, about 26 years, about 24years, about 22 years, about 20 years, about 18 years, about 16 years,about 14 years, about 12 years, about 10 years, about 9.5 years, about 9years, about 8.5 years, about 8 years, about 7.5 years, or about 7years, about 7 years to about 40 years, about 38 years, about 36 years,about 34 years, about 32 years, about 30 years, about 28 years, about 26years, about 24 years, about 22 years, about 20 years, about 18 years,about 16 years, about 14 years, about 12 years, about 10 years, about9.5 years, about 9 years, about 8.5 years, about 8 years, or about 7.5years; about 7.5 years to about 40 years, about 38 years, about 36years, about 34 years, about 32 years, about 30 years, about 28 years,about 26 years, about 24 years, about 22 years, about 20 years, about 18years, about 16 years, about 14 years, about 12 years, about 10 years,about 9.5 years, about 9 years, about 8.5 years, or about 8 years; about8 years to about 40 years, about 38 years, about 36 years, about 34years, about 32 years, about 30 years, about 28 years, about 26 years,about 24 years, about 22 years, about 20 years, about 18 years, about 16years, about 14 years, about 12 years, about 10 years, about 9.5 years,about 9 years, or about 8.5 years; about 8.5 years to about 40 years,about 38 years, about 36 years, about 34 years, about 32 years, about 30years, about 28 years, about 26 years, about 24 years, about 22 years,about 20 years, about 18 years, about 16 years, about 14 years, about 12years, about 10 years, about 9.5 years, or about 9 years; about 9 yearsto about 40 years, about 38 years, about 36 years, about 34 years, about32 years, about 30 years, about 28 years, about 26 years, about 24years, about 22 years, about 20 years, about 18 years, about 16 years,about 14 years, about 12 years, about 10 years, or about 9.5 years;about 9.5 years to about 40 years, about 38 years, about 36 years, about34 years, about 32 years, about 30 years, about 28 years, about 26years, about 24 years, about 22 years, about 20 years, about 18 years,about 16 years, about 14 years, about 12 years, or about 10 years; about10 years to about 40 years, about 38 years, about 36 years, about 34years, about 32 years, about 30 years, about 28 years, about 26 years,about 24 years, about 22 years, about 20 years, about 18 years, about 16years, about 14 years, or about 12 years; about 12 years to about 40years, about 38 years, about 36 years, about 34 years, about 32 years,about 30 years, about 28 years, about 26 years, about 24 years, about 22years, about 20 years, about 18 years, about 16 years, or about 14years; about 14 years to about 40 years, about 38 years, about 36 years,about 34 years, about 32 years, about 30 years, about 28 years, about 26years, about 24 years, about 22 years, about 20 years, about 18 years,or about 16 years; about 16 years to about 40 years, about 38 years,about 36 years, about 34 years, about 32 years, about 30 years, about 28years, about 26 years, about 24 years, about 22 years, about 20 years,or about 18 years; about 18 years to about 40 years, about 38 years,about 36 years, about 34 years, about 32 years, about 30 years, about 28years, about 26 years, about 24 years, about 22 years, or about 20years; about 20 years to about 40 years, about 38 years, about 36 years,about 34 years, about 32 years, about 30 years, about 28 years, about 26years, about 24 years, or about 22 years; about 22 years to about 40years, about 38 years, about 36 years, about 34 years, about 32 years,about 30 years, about 28 years, about 26 years, or about 24 years; about24 years to about 40 years, about 38 years, about 36 years, about 34years, about 32 years, about 30 years, about 28 years, or about 26years; about 26 years to about 40 years, about 38 years, about 36 years,about 34 years, about 32 years, about 30 years, or about 28 years; about28 years to about 40 years, about 38 years, about 36 years, about 34years, about 32 years, or about 30 years; about 30 years to about 40years, about 38 years, about 36 years, about 34 years, or about 32years; about 32 years to about 40 years, about 38 years, about 36 years,or about 34 years; about 34 years to about 40 years, about 38 years, orabout 36 years; about 36 years to about 40 years or about 38 years; orabout 38 years to about 40 years (e.g., compared to a control patient,e.g., a patient or a population of patients having the same or a similartype of FGFR-associated cancer).

Also provided is the use of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof for increasing thetime of survival of a patient having a FGFR-associated cancer. Alsoprovided is the use of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof for the manufacture of a medicamentfor increasing the time of survival of a patient having aFGFR-associated cancer.

Also provided are methods of increasing sensitivity of a resistantcancer cell to an anti-cancer drug that include: selecting, identifying,or diagnosing a patient as having a resistant cancer cell (e.g., aresistant FGFR-associated cancer cell, e.g., a cancer cell identified ashaving one or more of the point mutations listed in Table BE), andadministering to the selected, identified, or diagnosed subject atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof. Also provided aremethods of increasing sensitivity of a resistant cancer cell to ananti-cancer drug that include administering to a patient having aresistant cancer cell to an anti-cancer drug a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof. Some embodiments of any of these methods furtherinclude administering the anti-cancer drug to the patient. In suchexamples, the anti-cancer drug can be co-administered with the compoundof Formula I or a pharmaceutically acceptable salt or solvate thereof.In some examples, the anti-cancer drug can be administered atsubstantially the same time as the compound of Formula I or apharmaceutically acceptable salt or solvate thereof. In some examples, afirst dose of the compound of Formula I is administered prior to thefirst dose of the anti-cancer compound. In some examples, a first doseof the anti-cancer compound is administered prior to the first dose ofthe compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof. In some examples, the increase in the sensitivity ofthe resistant cancer cell to the anti-cancer drug can result in adecrease in the rate of growth and/or proliferation of the resistantcancer cell when contacted with the anti-cancer drug and at least one ofthe compounds described herein, of between about 1% to about 100%, 95%,90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%,20%, 15%, 10%, or 5%; about 2% to about 100%, 95%, 90%, 85%, 80%, 75%,70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5%;about 3% to about 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%,50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5%; about 5% to about100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%,30%, 25%, 20%, 15%, or 10%; about 5% to about 100%, 95%, 90%, 85%, 80%,75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or5%; about 5% to about 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%,50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10%; about 10% to about 100%,95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%,25%, 20%, 15%, 10%, or 5%; about 5% to about 100%, 95%, 90%, 85%, 80%,75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, or 15%;about 15% to about 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%,50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5%; about 5% to about100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%,30%, 25%, or 20%; about 20% to about 100%, 95%, 90%, 85%, 80%, 75%, 70%,65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5%; about5% to about 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%,40%, 35%, 30%, or 25%; about 25% to about 100%, 95%, 90%, 85%, 80%, 75%,70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, or 20%; about 20% toabout 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%,35%, 30%, 25%, 20%, 15%, 10%, or 5%; about 5% to about 100%, 95%, 90%,85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, or 30%; about 30%to about 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%,40%, or 35%; about 35% to 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%,55%, 50%, 45%, or 40%; about 40% to about 100%, 95%, 90%, 85%, 80%, 75%,70%, 65%, 60%, 55%, 50%, or 45%; about 45% to about 100%, 95%, 90%, 85%,80%, 75%, 70%, 65%, 60%, 55%, or 50%; about 50% to about 100%, 95%, 90%,85%, 80%, 75%, 70%, 65%, 60%, or 55%; about 55% to about 100%, 95%, 90%,85%, 80%, 75%, 70%, 65%, or 60%; about 60% to about 100%, 95%, 90%, 85%,80%, 75%, 70%, or 65%; about 65% to about 100%, 95%, 90%, 85%, 80%, 75%,or 70%; about 70% to about 100%, 95%, 90%, 85%, 80%, or 75%; about 75%to about 100%, 95%, 90%, 85%, or 80%; about 80% to about 100%, 95%, 90%,or 85%; about 85% to about 100%, 95%, or 90%; about 90% to about 100% or95%; or about 95% to about 100%, as compared to the rate of growthand/or proliferation of a resistant cancer cell when contacted with theanti-cancer drug alone.

Also provided herein are methods for reversing or preventing acquiredresistance to an anticancer drug, comprising administering atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof, to a patient atrisk for developing or having acquired resistance to an anticancer drug.In some embodiments, the patient is administered a dose of theanticancer drug (e.g., at substantially the same time as a dose of acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof is administered to the patient).

Also provided herein are methods of delaying and/or preventingdevelopment of cancer resistant to an anticancer drug in an individual,comprising concomitantly administering to the individual (a) aneffective amount of a compound of Formula I and (b) an effective amountof the anticancer drug.

Also provided herein are methods of treating a subject with cancer whohas increased likelihood of developing resistance to an anticancer drug,comprising concomitantly administering to the individual (a) aneffective amount of a compound of Formula I and (b) an effective amountof the anticancer drug.

In some embodiments, treatment with a first FGFR1 inhibitor (e.g., aFGFR inhibitor not of Formula I) can cause an elevated serum phosphatelevel (e.g., hyperphosphatemia) in a subject. Without being bound bytheory, it is believed that inhibition of FGFR1 causes an elevated serumphosphate level (e.g., hyperphosphatemia) by blocking FGF23 signaling(see, e.g., Ornitz and Itoh, Wiley Interdiscip Rev Dev Biol,4(3):215-266,2015; Erben and Andrukhova, Bone, 100:62-62,2017). Anelevated phosphate level can be determined in comparison to an earliertime point, e.g., before administration of the first dose of the firstFGFR1 inhibitor. An elevated phosphate level can be determined followingadministration of one or more doses of the first FGFR1 inhibitor, e.g.,about 1 day to about 12 days (e.g., about 1 day to about 2 days, about 1day to about 3 days about 1 day to about 4 days, about 1 day to about 5days, about 1 day to about 6 days, about 1 day to about 7 days, about 1day to about 8 days, about 1 day to about 9 days, about 1 day to about10 days, about 1 day to about 11 days, about 2 days to about 12 days,about 3 days to about 12 days, about 4 days to about 12 days, about 5days to about 12 days, about 6 days to about 12 days, about 7 days toabout 12 days, about 8 days to about 12 days, about 9 days to about 12days, about 10 days to about 12 days, about 11 days to about 12 days,about 1 day, about 2 days, about 3 days, about 4 days, about 5 days,about 6 days, about 7 days, about 8 days, about 9 days, about 10 days,about 11 days, or about 12 days following administration of one or moredoses of the first FGFR inhibitor. In some embodiments, a first FGFR1inhibitor is a FGFR inhibitor having FGFR1 activity at least one of:FGFR2 activity, FGFR3 activity, or FGFR4 activity. For example, a firstFGFR inhibitor can have a FGFR1 activity of less than about 500 nM in anin vitro FGFR1 kinase assay. An elevated phosphate level can also bedetermined in comparison to a reference value, e.g., an elevatedphosphate level can be at least or about 5.5 mg/dL, at least or about6.0 mg/dL, at least or about 6.5 mg/dL, at least or about 7.0 mg/dL, atleast or about 7.5 mg/dL, at least or about 8.0 mg/dL, at least or about8.5 mg/dL, at least or about 9.0 mg/dL, at least or about 9.5 mg/dL, atleast or about 10 mg/dL, at least or about 10.5 mg/dL, at least or about11 mg/dL, at least or about 11.5 mg/dL, at least or about 12 mg/dL, atleast or about 12.5 mg/dL, at least or about 13 mg/dL, at least or about13.5 mg/dL, at least or about 14 mg/dL, or at least or about 15 mg/dL.

In some embodiments, the presence of an elevated serum phosphate level(e.g., hyperphosphatemia) in a subject (e.g., a subject) can bedetermined by measuring a level(s) of phosphate in a biological sampleincluding blood, serum, or plasma (e.g., peripheral blood) obtained fromthe subject after a particular treatment period (e.g., any of thetreatment periods described herein). Determining the phosphate level inperipheral blood can be achieved using conventional methods known in theart (see, e.g., serum phosphate test offered, e.g., by the Mayo ClinicLaboratories, which utilizes the Roche Phosphorus reagent (RocheDiagnostics, Inc.; the test is based on the reaction of phosphate withammonium molybdate to form ammonium phosphomolybdate (withoutreduction)).

In certain embodiments, the serum phosphate level exhibited by a subject(e.g., a subject treated wth a first FGFR1 inhibitor) can be at least orabout 5 mg/dL, at least or about 5.5 mg/dL, at least or about 6.0 mg/dL,at least or about 6.5 mg/dL, at least or about 7.0 mg/dL, at least orabout 7.5 mg/dL, at least or about 8.0 mg/dL, at least or about 8.5mg/dL, at least or about 9.0 mg/dL, at least or about 9.5 mg/dL, atleast or about 10 mg/dL, at least or about 10.5 mg/dL, at least or about11 mg/dL, at least or about 11.5 mg/dL, at least or about 12 mg/dL atleast or about 12.5 mg/dL, at least or about 13 mg/dL, at least or about13.5 mg/dL, at least or about 14 mg/dL, or at least or about 15 mg/dL.In some embodiments, the reference level of phosphate can be the levelin a healthy subject or the average level in a population of healthysubjects (e.g., subjects not having an elevated serum phosphate level(e.g., hyperphosphatemia) or a subjects not at risk for developing anelevated phosphate level (e.g., hyperphosphatemia), such as those havinga serum phosphate level of from about 2.0 mg/dL to about 5.0 mg/dL;e.g., from about 2.5 mg/dL to about 4.5 mg/dL).

In some embodiments, a subject (e.g., a subject treated with a firstFGFR1 inhibitor) with an elevated phosphate level using methods providedherein can also exhibit one or both of: (i) a calcium-phosphate product(serum calcium in mg/dL×serum phosphate in mg/dL) of at least or about50 mg²/dL² (e.g., at least or about 52 mg²/dL², at least or about 54mg²/dL², at least or about 56 mg²/dL², at least or about 58 mg²/dL², atleast or about 60 mg²/dL², at least or about 62 mg²/dL², at least orabout 64 mg²/dL², at least or about 66 mg²/dL², at least or about 68mg²/dL², at least or about 70 mg²/dL², at least or about 72 mg²/dL², atleast or about 74 mg²/dL², at least or about 76 mg²/dL², at least orabout 78 mg²/dL², at least or about 80 mg²/dL², at least or about 82mg²/dL², at least or about 84 mg²/dL², at least or about 86 mg²/dL², atleast or about 88 mg²/dL², at least about 90 mg²/dL², at least or about92 mg²/dL², at least or about 94 mg²/dL², at least or about 96 mg²/dL²,at least about 98 mg²/dL², or at least about 100 mg²/dL²) in abiological sample and (ii) a serum creatinine level of grade 1 orgreater (e.g., grade 2, grade 3) in a biological sample. Exemplaryassays for determining the calcium level of a biological sampleincluding blood, serum, or plasma are commercially available fromBioVision Inc. (Milpitas, Calif.) and Sigma-Aldrich (St. Louis, Mo.).Exemplary assays for determining the creatinine level in a biologicalsample including blood, serum, or plasma are commercially available fromBioVision Inc. (Milpitas, Calif.) and Diazyme (Poway, Calif.). In someembodiments, the subject can exhibit a serum phosphate level of greaterthan about 7.0 mg/dL (e.g., a serum phosphate level of greater than 7mg/dL lasting for more than 7 days despite phosphate-loweringtherapies). In some embodiments, the subject exhibits a serum phosphatelevel of greater than about 9.0 mg/dL (e.g., a serum phosphate level ofgreater than about 9.0 mg/dL for any duration despite phosphate-loweringtherapies). In still other embodiments, the subject exhibits a serumphosphate level of greater than about 10.0 mg/dL (e.g., a serumphosphate level of greater than about 10.0 mg/dL for any duration).

In some embodiments of these methods, a subject can be administered aphosphate binder (e.g., any of the exemplary phosphate binders describedherein or known in the art). In some embodiments of these methods, thephosphate binder is sevelamer hydrochloride. In some embodiments ofthese methods, administration of the phosphate binder (e.g., sevelamerhydrochloride) can be a total daily administration of about 0.1 g toabout 2.0 g (e.g., about 0.1 g to about 1.9 g, about 1.8 g., about 1.7g, about 1.6 g, about 1.5 g, about 1.4 g, about 1.3 g, about 1.2 g,about 1.1 g, about 1.0 g, about 0.9 g, about 0.8 g, about 0.7 g, about0.6 g, about 0.5 g, about 0.4 g, about 0.3 g, or about 0.2 g; about 0.2g to about 1.9 g, about 1.8 g., about 1.7 g, about 1.6 g, about 1.5 g,about 1.4 g, about 1.3 g, about 1.2 g, about 1.1 g, about 1.0 g, about0.9 g, about 0.8 g, about 0.7 g, about 0.6 g, about 0.5 g, about 0.4 g,or about 0.3 g; about 0.3 g to about 1.9 g, about 1.8 g., about 1.7 g,about 1.6 g, about 1.5 g, about 1.4 g, about 1.3 g, about 1.2 g, about1.1 g, about 1.0 g, about 0.9 g, about 0.8 g, about 0.7 g, about 0.6 g,about 0.5 g, or about 0.4 g; about 0.4 g to about 1.9 g, about 1.8 g.,about 1.7 g, about 1.6 g, about 1.5 g, about 1.4 g, about 1.3 g, about1.2 g, about 1.1 g, about 1.0 g, about 0.9 g, about 0.8 g, about 0.7 g,about 0.6 g, or about 0.5 g; about 0.5 g to about 1.9 g, about 1.8 g.,about 1.7 g, about 1.6 g, about 1.5 g, about 1.4 g, about 1.3 g, about1.2 g, about 1.1 g, about 1.0 g, about 0.9 g, about 0.8 g, about 0.7 g,or about 0.6 g; about 0.6 g to about 1.9 g, about 1.8 g., about 1.7 g,about 1.6 g, about 1.5 g, about 1.4 g, about 1.3 g, about 1.2 g, about1.1 g, about 1.0 g, about 0.9 g, about 0.8 g, or about 0.7 g; about 0.7g to about 1.9 g, about 1.8 g., about 1.7 g, about 1.6 g, about 1.5 g,about 1.4 g, about 1.3 g, about 1.2 g, about 1.1 g, about 1.0 g, about0.9 g, or about 0.8 g; about 0.8 g to about 1.9 g, about 1.8 g., about1.7 g, about 1.6 g, about 1.5 g, about 1.4 g, about 1.3 g, about 1.2 g,about 1.1 g, about 1.0 g, or about 0.9 g; about 0.9 g to about 1.9 g,about 1.8 g., about 1.7 g, about 1.6 g, about 1.5 g, about 1.4 g, about1.3 g, about 1.2 g, about 1.1 g, or about 1.0 g; about 1.0 g to about1.9 g, about 1.8 g., about 1.7 g, about 1.6 g, about 1.5 g, about 1.4 g,about 1.3 g, about 1.2 g, or about 1.1 g; about 1.1 g to about 1.9 g,about 1.8 g., about 1.7 g, about 1.6 g, about 1.5 g, about 1.4 g, about1.3 g, or about 1.2 g; about 1.2 g to about 1.9 g, about 1.8 g., about1.7 g, about 1.6 g, about 1.5 g, about 1.4 g, or about 1.3 g; about 1.3g to about 1.9 g, about 1.8 g., about 1.7 g, about 1.6 g, about 1.5 g,or about 1.4 g; about 1.4 g to about 1.9 g, about 1.8 g., about 1.7 g,about 1.6 g, or about 1.5 g; about 1.5 g to about 1.9 g, about 1.8 g.,about 1.7 g, or about 1.6 g; about 1.6 g to about 1.9 g, about 1.8 g.,or about 1.7 g; about 1.7 g to about 2.0 g, about 1.9 g, or about 1.8 g;about 1.8 g to about 2.0 g or about 1.9 g; or about 1.9 g to about 2.0g) of the phosphate binder.

In some embodiments, the subject is determined to have about the same ora decreased level of phosphate in one or more (e.g., two, three, four,five, or six) sample(s) including blood, serum, or plasma obtained fromthe subject at 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days (1week), 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days (2weeks), 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days,22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days,30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days,38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days,46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days,54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 61 days,62 days, 63 days, 64 days, 65 days, 66 days, 67 days, 68 days, 69 days,70 days, 71 days, 72 days, 73 days, 74 days, 75 days, 76 days, 77 days,78 days, 79 days, 80 days, 81 days, 82 days, 83 days, 84 days, 85 days,86 days, 87 days, 88 days, 89 days, 90 days, 91 days, 92 days, 93 days,94 days, 95 days, 96 days, 97 days, 98 days, 99 days, or 100 daysfollowing the start of the administration of a therapeutic (e.g., afirst FGFR1 inhibitor with or without a phosphate binder, a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof) ascompared to a reference level of phosphate (e.g., any of the referencelevels of phosphate described herein).

In some embodiments, a subject is administered a therapeuticallyeffective amount of a phosphate binder. Non-limiting examples ofphosphate binders include aluminum salts (e.g., Alucaps and Basaljel),calcium carbonate (e.g., Calcichew and Titralac), calcium acetate (e.g.,Lenal Ace and PhosLo), sevelamer hydrochloride (e.g., Renegel orRenvela), and lanthanum carbonate (e.g., Fosrenol). A phosphate bindercan be administered at a total daily dose of about 2.0 g to about 5.0 g(e.g., about 2.0 g to about 4.8 g, about 4.6 g, about 4.4 g, about 4.2g, about 4.0 g, about 3.8 g, about 3.6 g, about 3.4 g, about 3.2 g,about 3.0 g, about 2.8 g, about 2.6 g, about 2.4 g, or about 2.2 g;about 2.2 g to about 5.0 g, about 4.8 g, about 4.6 g, about 4.4 g, about4.2 g, about 4.0 g, about 3.8 g, about 3.6 g, about 3.4 g, about 3.2,about 3.0 g, about 2.8 g, about 2.6 g, or about 2.4 g; about 2.4 toabout 5.0 g, about 4.8 g, about 4.6 g, about 4.4 g, about 4.2 g, about4.0 g, about 3.8 g, about 3.6 g, about 3.4 g, about 3.2, about 3.0 g,about 2.8 g, or about 2.6 g; about 2.6 g to about 5.0 g, about 4.8 g,about 4.6 g, about 4.4 g, about 4.2 g, about 4.0 g, about 3.8 g, about3.6 g, about 3.4 g, about 3.2, about 3.0 g, or about 2.8 g; about 2.8 gto about 5.0 g, about 4.8 g, about 4.6 g, about 4.4 g, about 4.2 g,about 4.0 g, about 3.8 g, about 3.6 g, about 3.4 g, about 3.2, or about3.0 g; about 3.0 g to about 5.0 g, about 4.8 g, about 4.6 g, about 4.4g, about 4.2 g, about 4.0 g, about 3.8 g, about 3.6 g, about 3.4 g, orabout 3.2 g; about 3.2 g to about 5.0 g, about 4.8 g, about 4.6 g, about4.4 g, about 4.2 g, about 4.0 g, about 3.8 g, about 3.6 g, or about 3.4g; about 3.4 g to about 5.0 g, about 4.8 g, about 4.6 g, about 4.4 g,about 4.2 g, about 4.0 g, about 3.8 g, or about 3.6 g; about 3.6 g toabout 5.0 g, about 4.8 g, about 4.6 g, about 4.4 g, about 4.2 g, about4.0 g, or about 3.8 g; about 3.8 g to about 5.0 g, about 4.8 g, about4.6 g, about 4.4 g, about 4.2 g, or about 4.0 g; about 4.0 g to about5.0 g, about 4.8 g, about 4.6 g, about 4.4 g, or about 4.2 g; about 4.2g to about 5.0 g, about 4.8 g, about 4.6 g, or about 4.4 g; about 4.4 gto about 5.0 g, about 4.8 g, or about 4.6 g; about 4.6 g to about 5.0 gor about 4.8 g; or about 4.8 g to about 5.0 g). In some embodiments ofany of the methods described herein, the method further comprisesadministering a phosphate binder to the subject. In some embodiments ofthese methods, the method further includes ceasing administration of thephosphate binder to a subject or instructing a subject to ceaseadministration of the phosphate binder. In some embodiments of thesemethods, the method further includes administering a decreased dose ofthe phosphate binder to a subject relative to a dose of the phosphatebinder previously administered to the subject.

In some embodiments of any of the methods described herein, a subject isnot administered a phosphate binder.

Methods useful when a subject has elevated blood phosphate levels aredescribed below. For example, provided herein are methods of treating asubject having a cancer that include: identifying a subjectdemonstrating an elevated phosphate level and a FGFR-associated cancer(e.g., any of the FGFR-associated cancers described herein or known inthe art); and administering to the identified subject a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the identifying step comprises identifying a subjectexhibiting an elevated phosphate level and at least one of: (i) acalcium-phosphate product of at least about 50 mg²/dL² and (ii) a serumcreatinine level of grade 1 or greater. Also provided are methods oftreating a subject identified as having an elevated phosphate level anda FGFR-associated cancer (e.g., any of the FGFR-associated cancersdescribed herein or known in the art) that include administering to thesubject a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments, the identified subject alsoexhibits at least one of: (i) a calcium-phosphate product of at leastabout 50 mg²/dL² and (i) a serum creatinine level of grade 1 or greater.In some embodiments, demonstration of an elevated phosphate level occursabout 1 day to about 12 days (e.g., about 1 day to about 2 days, about 1day to about 3 days about 1 day to about 4 days, about 1 day to about 5days, about 1 day to about 6 days, about 1 day to about 7 days, about 1day to about 8 days, about 1 day to about 9 days, about 1 day to about10 days, about 1 day to about 11 days, about 2 days to about 12 days,about 3 days to about 12 days, about 4 days to about 12 days, about 5days to about 12 days, about 6 days to about 12 days, about 7 days toabout 12 days, about 8 days to about 12 days, about 9 days to about 12days, about 10 days to about 12 days, about 11 days to about 12 days,about 1 day, about 2 days, about 3 days, about 4 days, about 5 days,about 6 days, about 7 days, about 8 days, about 9 days, about 10 days,about 11 days, or about 12 days) following administration of one or moredoses of a first FGFR inhibitor. In some embodiments, an elevatedphosphate level is a phosphate level (e.g., in a blood sample) of atleast about 5 mg/dL (e.g., at least about 5.5 mg/dL, 6.0 mg/dL, 6.5mg/dL, 7.0 mg/dL, 7.5 mg/dL, 8.0 mg/dL, 8.5 mg/dL, 9.0 mg/dL, 9.5 mg/dL,or 10.0 mg/dL). In some embodiments, demonstration of an elevatedphosphate level comprises demonstrating an elevated phosphate level andat least one of: (i) a calcium-phosphate product of at least about 50mg²/dL² and (ii) a serum creatinine level of grade 1 or greater. In someembodiments, an elevated phosphate level is demonstrated in comparisonto an earlier sample from the same subject (e.g., before administrationof one or more doses of a first FGFR1 inhibitor). In some embodiments,the first FGFR1 inhibitor has a FGFR1 activity of less than about 500 nMin an in vitro FGFR1 kinase assay.

For example, provided herein are methods for treating a FGFR-associatedcancer in a subject in need of such treatment, the method comprising (a)detecting a dysregulation of a FGFR gene, a FGFR kinase, or theexpression or activity or level of any of the same in a sample from thesubject; and (b) administering to the subject a therapeuticallyeffective amount of a first FGFR1 inhibitor. In some embodiments, themethods further comprise (after (b)) (c) determining whether a samplefrom a subject demonstrates an elevated phosphate level; and (d)administering a compound of Formula I, or a pharmaceutically acceptablesalt or solvate thereof as a monotherapy or in conjunction with anadditional therapy or therapeutic agent to the subject if the samplefrom the subject demonstrates an elevated phosphate level; or (e)administering additional doses of the first FGFR1 inhibitor of step (b)to the subject if the sample from the subject does not demonstrate anelevated phosphate level. In some embodiments, the methods furthercomprise (after (b)) (c) determining whether a sample from a subjectdemonstrates an elevated phosphate level and least one of: (i) acalcium-phosphate product of at least about 50 mg²/dL² and (ii) a serumcreatinine level of grade 1 or greater; and (d) administering a compoundof Formula I, or a pharmaceutically acceptable salt or solvate thereofas a monotherapy or in conjunction with an additional therapy ortherapeutic agent to the subject if the sample from the subjectdemonstrates an elevated phosphate level and least one of: (i) acalcium-phosphate product of at least about 50 mg²/dL² and (ii) a serumcreatinine level of grade 1 or greater; or (e) administering additionaldoses of the first FGFR1 inhibitor of step (b) to the subject if thesample from the subject does not demonstrate an elevated phosphate leveland at least one of: (i) a calcium-phosphate product of at least about50 mg²/dL² and (2) a serum creatinine level of grade 1 or greater. Insome embodiments, when the method comprises administering a compound ofFormula I, the method further comprises (f) determining that a samplefrom the subject does not demonstrate an elevated phosphate level. Insome embodiments, the FGFR1 inhibitor of step (b) is selected from thegroup consisting of ARQ-087, ASP5878, AZD4547, BGJ398, brivanib, Debio1347, dovitinib, E7090, erdafitinib, HMPL-453, INCB054828, lenvatinib,lucitanib, MAX-40279, nintedanib, orantinib, pemigatinib, ponatinib,PRN1371, rogaratinib, sulfatinib, and TAS-120. In some embodiments, thesample of step (c) is a blood sample. In some embodiments of any ofthese methods, step (b) further includes administering to the subject aphosphate binder. In some embodiments, step (c) occurs about 1 to about12 days (e.g., about 1 day to about 2 days, about 1 day to about 3 days,about 1 day to about 4 days, about 1 day to about 5 days, about 1 day toabout 6 days, about 1 day to about 7 days, about 1 day to about 8 days,about 1 day to about 9 days, about 1 day to about 10 days, about 1 dayto about 11 days, about 2 days to about 12 days, about 3 days to about12 days, about 4 days to about 12 days, about 5 days to about 12 days,about 6 days to about 12 days, about 7 days to about 12 days, about 8days to about 12 days, about 9 days to about 12 days, about 10 days toabout 12 days, about 11 days to about 12 days, about 1 day, about 2days, about 3 days, about 4 days, about 5 days, about 6 days, about 7days, about 8 days, about 9 days, about 10 days, about 11 days, or about12 days) after step (b). In some embodiments, an elevated phosphatelevel is a phosphate level (e.g., in a blood sample) of at least about 5mg/dL (e.g., at least about 5.5 mg/dL, 6.0 mg/dL, 6.5 mg/dL, 7.0 mg/dL,7.5 mg/dL, 8.0 mg/dL, 8.5 mg/dL, 9.0 mg/dL, 9.5 mg/dL, or 10.0 mg/dL).In some embodiments, demonstration of an elevated phosphate levelcomprises demonstrating an elevated phosphate level and at least one of:(i) a calcium-phosphate product of at least about 50 mg²/dL² and (ii) aserum creatinine level of grade 1 or greater. In some embodiments, anelevated phosphate level is demonstrated in comparison to an earliersample from the same subject (e.g., before administration of one or moredoses of a first FGFR1 inhibitor). In some embodiments, the first FGFR1inhibitor has a FGFR activity of less than about 500 nM in an in vitroFGFR1 kinase assay. In some embodiments, demonstration of a phosphatelevel that is not an elevated phosphate level occurs about 6 hours,about 12 hours, about 18 hours, about 1 day, about 1.5 days, about 2days, about 3 days, about 4 days, about 5 days, about 6 days, about 7days, about 8 days, about 9 days, about 10 days, about 2 weeks, about 3weeks, or about 4 weeks after administration of one or more doses of thecompound of Formula I. In some embodiments, a phosphate level that isnot an elevated phosphate level (e.g., in a blood sample) is a phosphatelevel of at between about 2.5 and about 4.5 mg/dL (e.g., between about2.5 and about 3.0 mg/dL, about 2.5 and about 3.5 mg/dL, about 2.5 andabout 4.0 mg/dL, about 3.0 to about 4.5 mg/dL, about 3.5 to about 4.5mg/dL, or about 4.0 to about 4.5 mg/dL). In some embodiments, aphosphate level that is not an elevated phosphate level (e.g., in ablood sample) is a phosphate level of at less than about 5 mg/dL (e.g.,less than about 4.5 mg/dL, 4.0 mg/dL, 3.5 mg/dL, or 3.0 mg/dL, or 2.5 mgd/L). In some embodiments, an additional therapy or therapeutic agent isnot an FGFR1 inhibitor.

For example, provided herein are methods for treating a FGFR-associatedcancer in a subject in need of such treatment, the method comprising (a)detecting a dysregulation of a FGFR gene, a FGFR kinase, or theexpression or activity or level of any of the same in a sample from thesubject; and (b) administering to the subject a therapeuticallyeffective amount of a first FGFR1 inhibitor. In some embodiments, themethods further comprise (after (b)) (c) determining whether a samplefrom a subject demonstrates an elevated phosphate level; and (d)administering a compound of Formula I selected from Examples 1-30, or apharmaceutically acceptable salt or solvate thereof as a monotherapy orin conjunction with an additional therapy or therapeutic agent to thesubject if the sample from the subject demonstrates an elevatedphosphate level; or (e) administering additional doses of the firstFGFR1 inhibitor of step (b) to the subject if the sample from thesubject does not demonstrate an elevated phosphate level. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a sample from a subject demonstrates an elevated phosphate leveland least one of: (i) a calcium-phosphate product of at least about 50mg²/dL² and (ii) a serum creatinine level of grade 1 or greater; and (d)administering a compound of Formula I selected from Examples 1-30, or apharmaceutically acceptable salt or solvate thereof as a monotherapy orin conjunction with an additional therapy or therapeutic agent to thesubject if the sample from the subject demonstrates an elevatedphosphate level and least one of: (i) a calcium-phosphate product of atleast about 50 mg²/dL² and (ii) a serum creatinine level of grade 1 orgreater; or (e) administering additional doses of the first FGFR1inhibitor of step (b) to the subject if the sample from the subject doesnot demonstrate an elevated phosphate level and at least one of: (i) acalcium-phosphate product of at least about 50 mg²/dL² and (2) a serumcreatinine level of grade 1 or greater. In some embodiments, when themethod comprises administering a compound of Formula I selected fromExamples 1-30, the method further comprises (f) determining that asample from the subject does not demonstrate an elevated phosphatelevel. In some embodiments, the FGFR1 inhibitor of step (b) is selectedfrom the group consisting of ARQ-087, ASP5878, AZD4547, BGJ398,brivanib, Debio 1347, dovitinib, E7090, erdafitinib, HMPL-453,INCB054828, lenvatinib, lucitanib, MAX-40279, nintedanib, orantinib,pemigatinib, ponatinib, PRN1371, rogaratinib, sulfatinib, and TAS-120.In some embodiments, the sample of step (c) is a blood sample. In someembodiments of any of these methods, step (b) further includesadministering to the subject a phosphate binder. In some embodiments,step (c) occurs about 1 to about 12 days (e.g., about 1 day to about 2days, about 1 day to about 3 days, about 1 day to about 4 days, about 1day to about 5 days, about 1 day to about 6 days, about 1 day to about 7days, about 1 day to about 8 days, about 1 day to about 9 days, about 1day to about 10 days, about 1 day to about 11 days, about 2 days toabout 12 days, about 3 days to about 12 days, about 4 days to about 12days, about 5 days to about 12 days, about 6 days to about 12 days,about 7 days to about 12 days, about 8 days to about 12 days, about 9days to about 12 days, about 10 days to about 12 days, about 11 days toabout 12 days, about 1 day, about 2 days, about 3 days, about 4 days,about 5 days, about 6 days, about 7 days, about 8 days, about 9 days,about 10 days, about 11 days, or about 12 days) after step (b). In someembodiments, an elevated phosphate level is a phosphate level (e.g., ina blood sample) of at least about 5 mg/dL (e.g., at least about 5.5mg/dL, 6.0 mg/dL, 6.5 mg/dL, 7.0 mg/dL, 7.5 mg/dL, 8.0 mg/dL, 8.5 mg/dL,9.0 mg/dL, 9.5 mg/dL, or 10.0 mg/dL). In some embodiments, demonstrationof an elevated phosphate level comprises demonstrating an elevatedphosphate level and at least one of: (i) a calcium-phosphate product ofat least about 50 mg²/dL² and (ii) a serum creatinine level of grade 1or greater. In some embodiments, an elevated phosphate level isdemonstrated in comparison to an earlier sample from the same subject(e.g., before administration of one or more doses of a first FGFR1inhibitor). In some embodiments, the first FGFR1 inhibitor has a FGFR1activity of less than about 500 nM in an in vitro FGFR1 kinase assay. Insome embodiments, demonstration of a phosphate level that is not anelevated phosphate level occurs about 6 hours, about 12 hours, about 18hours, about 1 day, about 1.5 days, about 2 days, about 3 days, about 4days, about 5 days, about 6 days, about 7 days, about 8 days, about 9days, about 10 days, about 2 weeks, about 3 weeks, or about 4 weeksafter administration of one or more doses of the compound of Formula Iselected from Examples 1-30. In some embodiments, a phosphate level thatis not an elevated phosphate level (e.g., in a blood sample) is aphosphate level of at between about 2.5 and about 4.5 mg/dL (e.g.,between about 2.5 and about 3.0 mg/dL, about 2.5 and about 3.5 mg/dL,about 2.5 and about 4.0 mg/dL, about 3.0 to about 4.5 mg/dL, about 3.5to about 4.5 mg/dL, or about 4.0 to about 4.5 mg/dL). In someembodiments, a phosphate level that is not an elevated phosphate level(e.g., in a blood sample) is a phosphate level of at less than about 5mg/dL (e.g., less than about 4.5 mg/dL, 4.0 mg/dL, 3.5 mg/dL, or 3.0mg/dL, or 2.5 mg d/L). In some embodiments, an additional therapy ortherapeutic agent is not an FGFR1 inhibitor.

In some embodiments, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting one or more fusion proteins of Table BAand/or one or more FGFR kinase protein pointmutations/insertions/deletions of Table BC in a sample from the subject;and (b) administering to the subject a therapeutically effective amountof a first FGFR1 inhibitor. In some embodiments, the methods furthercomprise (after (b)) (c) determining whether a sample from a subjectdemonstrates an elevated phosphate level; and (d) administering acompound of Formula I, or a pharmaceutically acceptable salt or solvatethereof as a monotherapy or in conjunction with an additional therapy ortherapeutic agent to the subject if the sample from the subjectdemonstrates an elevated phosphate level; or (e) administeringadditional doses of the first FGFR1 inhibitor of step (b) to the subjectif the sample from the subject does not demonstrate an elevatedphosphate level. In some embodiments, the methods further comprise(after (b)) (c) determining whether a sample from a subject demonstratesan elevated phosphate level and least one of: (i) a calcium-phosphateproduct of at least about 50 mg²/dL² and (ii) a serum creatinine levelof grade 1 or greater; and (d) administering a compound of Formula I, ora pharmaceutically acceptable salt or solvate thereof as a monotherapyor in conjunction with an additional therapy or therapeutic agent to thesubject if the sample from the subject demonstrates an elevatedphosphate level and least one of: (i) a calcium-phosphate product of atleast about 50 mg²/dL² and (ii) a serum creatinine level of grade 1 orgreater; or (e) administering additional doses of the first FGFR1inhibitor of step (b) to the subject if the sample from the subject doesnot demonstrate an elevated phosphate level and least one of: (i) acalcium-phosphate product of at least about 50 mg²/dL² and (ii) a serumcreatinine level of grade 1 or greater. In some embodiments, when themethod comprises administering a compound of Formula I, the methodfurther comprises (f) determining that a sample from the subject doesnot demonstrate an elevated phosphate level. In some embodiments, theFGFR1 inhibitor of step (b) is selected from the group consisting ofARQ-087, ASP5878, AZD4547, BGJ398, brivanib, Debio 1347, dovitinib,E7090, erdafitinib, HMPL-453, INCB054828, lenvatinib, lucitanib,MAX-40279, nintedanib, orantinib, pemigatinib, ponatinib, PRN1371,rogaratinib, sulfatinib, and TAS-120. In some embodiments, the sample ofstep (c) is a blood sample. In some embodiments of any of these methods,step (b) further includes administering to the subject a phosphatebinder. In some embodiments, step (c) occurs about 1 to about 12 days(e.g., about 1 day to about 2 days, about 1 day to about 3 days, about 1day to about 4 days, about 1 day to about 5 days, about 1 day to about 6days, about 1 day to about 7 days, about 1 day to about 8 days, about 1day to about 9 days, about 1 day to about 10 days, about 1 day to about11 days, about 2 days to about 12 days, about 3 days to about 12 days,about 4 days to about 12 days, about 5 days to about 12 days, about 6days to about 12 days, about 7 days to about 12 days, about 8 days toabout 12 days, about 9 days to about 12 days, about 10 days to about 12days, about 11 days to about 12 days, about 1 day, about 2 days, about 3days, about 4 days, about 5 days, about 6 days, about 7 days, about 8days, about 9 days, about 10 days, about 11 days, or about 12 days)after step (b). In some embodiments, an elevated phosphate level is aphosphate level (e.g., in a blood sample) of at least about 5 mg/dL(e.g., at least about 5.5 mg/dL, 6.0 mg/dL, 6.5 mg/dL, 7.0 mg/dL, 7.5mg/dL, 8.0 mg/dL, 8.5 mg/dL, 9.0 mg/dL, 9.5 mg/dL, or 10.0 mg/dL). Insome embodiments, demonstration of an elevated phosphate level comprisesdemonstrating an elevated phosphate level and at least one of: (i) acalcium-phosphate product of at least about 50 mg²/dL² and (ii) a serumcreatinine level of grade 1 or greater. In some embodiments, an elevatedphosphate level is demonstrated in comparison to an earlier sample fromthe same subject (e.g., before administration of one or more doses of afirst FGFR1 inhibitor). In some embodiments, the first FGFR1 inhibitorhas a FGFR1 activity of less than about 500 nM in an in vitro FGFR1kinase assay. In some embodiments, demonstration of a phosphate levelthat is not an elevated phosphate level occurs about 6 hours, about 12hours, about 18 hours, about 1 day, about 1.5 days, about 2 days, about3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8days, about 9 days, about 10 days, about 2 weeks, about 3 weeks, orabout 4 weeks after administration of one or more doses of the compoundof Formula I. In some embodiments, a phosphate level that is not anelevated phosphate level (e.g., in a blood sample) is a phosphate levelof at between about 2.5 and about 4.5 mg/dL (e.g., between about 2.5 andabout 3.0 mg/dL, about 2.5 and about 3.5 mg/dL, about 2.5 and about 4.0mg/dL, about 3.0 to about 4.5 mg/dL, about 3.5 to about 4.5 mg/dL, orabout 4.0 to about 4.5 mg/dL). In some embodiments, a phosphate levelthat is not an elevated phosphate level (e.g., in a blood sample) is aphosphate level of at less than about 5 mg/dL (e.g., less than about 4.5mg/dL, 4.0 mg/dL, 3.5 mg/dL, or 3.0 mg/dL, or 2.5 mg d/L). In someembodiments, an additional therapy or therapeutic agent is not an FGFR1inhibitor.

In some embodiments, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting one or more fusion proteins of Table BAand/or one or more FGFR kinase protein pointmutations/insertions/deletions of Table BC in a sample from the subject;and (b) administering to the subject a therapeutically effective amountof a first FGFR1 inhibitor. In some embodiments, the methods furthercomprise (after (b)) (c) determining whether a sample from a subjectdemonstrates an elevated phosphate level; and (d) administering acompound of Formula I selected from Examples 1-30, or a pharmaceuticallyacceptable salt or solvate thereof as a monotherapy or in conjunctionwith an additional therapy or therapeutic agent to the subject if thesample from the subject demonstrates an elevated phosphate level; or (e)administering additional doses of the first FGFR1 inhibitor of step (b)to the subject if the sample from the subject does not demonstrate anelevated phosphate level. In some embodiments, the methods furthercomprise (after (b)) (c) determining whether a sample from a subjectdemonstrates an elevated phosphate level and least one of: (i) acalcium-phosphate product of at least about 50 mg²/dL² and (ii) a serumcreatinine level of grade 1 or greater; and (d) administering a compoundof Formula I selected from Examples 1-30, or a pharmaceuticallyacceptable salt or solvate thereof as a monotherapy or in conjunctionwith an additional therapy or therapeutic agent to the subject if thesample from the subject demonstrates an elevated phosphate level andleast one of: (i) a calcium-phosphate product of at least about 50mg²/dL² and (ii) a serum creatinine level of grade 1 or greater; or (e)administering additional doses of the first FGFR1 inhibitor of step (b)to the subject if the sample from the subject does not demonstrate anelevated phosphate level and least one of: (i) a calcium-phosphateproduct of at least about 50 mg²/dL² and (ii) a serum creatinine levelof grade 1 or greater. In some embodiments, when the method comprisesadministering a compound of Formula I selected from Examples 1-30, themethod further comprises (f) determining that a sample from the subjectdoes not demonstrate an elevated phosphate level. In some embodiments,the FGFR1 inhibitor of step (b) is selected from the group consisting ofARQ-087, ASP5878, AZD4547, BGJ398, brivanib, Debio 1347, dovitinib,E7090, erdafitinib, HMPL-453, INCB054828, lenvatinib, lucitanib,MAX-40279, nintedanib, orantinib, pemigatinib, ponatinib, PRN1371,rogaratinib, sulfatinib, and TAS-120. In some embodiments, the sample ofstep (c) is a blood sample. In some embodiments of any of these methods,step (b) further includes administering to the subject a phosphatebinder. In some embodiments, step (c) occurs about 1 to about 12 days(e.g., about 1 day to about 2 days, about 1 day to about 3 days, about 1day to about 4 days, about 1 day to about 5 days, about 1 day to about 6days, about 1 day to about 7 days, about 1 day to about 8 days, about 1day to about 9 days, about 1 day to about 10 days, about 1 day to about11 days, about 2 days to about 12 days, about 3 days to about 12 days,about 4 days to about 12 days, about 5 days to about 12 days, about 6days to about 12 days, about 7 days to about 12 days, about 8 days toabout 12 days, about 9 days to about 12 days, about 10 days to about 12days, about 11 days to about 12 days, about 1 day, about 2 days, about 3days, about 4 days, about 5 days, about 6 days, about 7 days, about 8days, about 9 days, about 10 days, about 11 days, or about 12 days)after step (b). In some embodiments, an elevated phosphate level is aphosphate level (e.g., in a blood sample) of at least about 5 mg/dL(e.g., at least about 5.5 mg/dL, 6.0 mg/dL, 6.5 mg/dL, 7.0 mg/dL, 7.5mg/dL, 8.0 mg/dL, 8.5 mg/dL, 9.0 mg/dL, 9.5 mg/dL, or 10.0 mg/dL). Insome embodiments, demonstration of an elevated phosphate level comprisesdemonstrating an elevated phosphate level and at least one of: (i) acalcium-phosphate product of at least about 50 mg²/dL² and (ii) a serumcreatinine level of grade 1 or greater. In some embodiments, an elevatedphosphate level is demonstrated in comparison to an earlier sample fromthe same subject (e.g., before administration of one or more doses of afirst FGFR1 inhibitor). In some embodiments, the first FGFR1 inhibitorhas a FGFR1 activity of less than about 500 nM in an in vitro FGFR1kinase assay. In some embodiments, demonstration of a phosphate levelthat is not an elevated phosphate level occurs about 6 hours, about 12hours, about 18 hours, about 1 day, about 1.5 days, about 2 days, about3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8days, about 9 days, about 10 days, about 2 weeks, about 3 weeks, orabout 4 weeks after administration of one or more doses of the compoundof Formula I selected from Examples 1-30. In some embodiments, aphosphate level that is not an elevated phosphate level (e.g., in ablood sample) is a phosphate level of at between about 2.5 and about 4.5mg/dL (e.g., between about 2.5 and about 3.0 mg/dL, about 2.5 and about3.5 mg/dL, about 2.5 and about 4.0 mg/dL, about 3.0 to about 4.5 mg/dL,about 3.5 to about 4.5 mg/dL, or about 4.0 to about 4.5 mg/dL). In someembodiments, a phosphate level that is not an elevated phosphate level(e.g., in a blood sample) is a phosphate level of at less than about 5mg/dL (e.g., less than about 4.5 mg/dL, 4.0 mg/dL, 3.5 mg/dL, or 3.0mg/dL, or 2.5 mg d/L). In some embodiments, an additional therapy ortherapeutic agent is not an FGFR1 inhibitor.

In some embodiments, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting the fusion protein FGFR3-TACC3 in asample from the subject; and (b) administering to the subject atherapeutically effective amount of a first FGFR1 inhibitor. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a sample from a subject demonstrates an elevated phosphatelevel; and (d) administering a compound of Formula I or apharmaceutically acceptable salt or solvate thereof selected from thegroup consisting of a compound of Formula I, or a pharmaceuticallyacceptable salt or solvate thereof as a monotherapy or in conjunctionwith an additional therapy or therapeutic agent to the subject if thesample from the subject demonstrates an elevated phosphate level; or (e)administering additional doses of the first FGFR1 inhibitor of step (b)to the subject if the sample from the subject does not demonstrate anelevated phosphate level. In some embodiments, the methods furthercomprise (after (b)) (c) determining whether a sample from a subjectdemonstrates an elevated phosphate level and least one of: (i) acalcium-phosphate product of at least about 50 mg²/dL² and (ii) a serumcreatinine level of grade 1 or greater; and (d) administering a compoundof Formula I or a pharmaceutically acceptable salt or solvate thereofselected from the group consisting of a compound of Formula I, or apharmaceutically acceptable salt or solvate thereof as a monotherapy orin conjunction with an additional therapy or therapeutic agent to thesubject if the sample from the subject demonstrates an elevatedphosphate level and least one of: (i) a calcium-phosphate product of atleast about 50 mg²/dL² and (ii) a serum creatinine level of grade 1 orgreater; or (e) administering additional doses of the first FGFR1inhibitor of step (b) to the subject if the sample from the subject doesnot demonstrate an elevated phosphate level and least one of: (i) acalcium-phosphate product of at least about 50 mg²/dL² and (ii) a serumcreatinine level of grade 1 or greater. In some embodiments, when themethod comprises administering a compound of Formula I, the methodfurther comprises (f) determining that a sample from the subject doesnot demonstrate an elevated phosphate level. In some embodiments, theFGFR1 inhibitor of step (b) is selected from the group consisting ofARQ-087, ASP5878, AZD4547, BGJ398, brivanib, Debio 1347, dovitinib,E7090, erdafitinib, HMPL-453, INCB054828, lenvatinib, lucitanib,MAX-40279, nintedanib, orantinib, pemigatinib, ponatinib, PRN1371,rogaratinib, sulfatinib, and TAS-120. In some embodiments, the sample ofstep (c) is a blood sample. In some embodiments of any of these methods,step (b) further includes administering to the subject a phosphatebinder. In some embodiments, a compound of Formula I is at least about3-fold more selective for FGFR3 over FGFR1. In some embodiments, acompound of Formula I is at least about 3-fold more selective for FGFR2over FGFR1. In some embodiments, step (c) occurs about 1 to about 12days (e.g., about 1 day to about 2 days, about 1 day to about 3 days,about 1 day to about 4 days, about 1 day to about 5 days, about 1 day toabout 6 days, about 1 day to about 7 days, about 1 day to about 8 days,about 1 day to about 9 days, about 1 day to about 10 days, about 1 dayto about 11 days, about 2 days to about 12 days, about 3 days to about12 days, about 4 days to about 12 days, about 5 days to about 12 days,about 6 days to about 12 days, about 7 days to about 12 days, about 8days to about 12 days, about 9 days to about 12 days, about 10 days toabout 12 days, about 11 days to about 12 days, about 1 day, about 2days, about 3 days, about 4 days, about 5 days, about 6 days, about 7days, about 8 days, about 9 days, about 10 days, about 11 days, or about12 days) after step (b). In some embodiments, an elevated phosphatelevel is a phosphate level (e.g., in a blood sample) of at least about 5mg/dL (e.g., at least about 5.5 mg/dL, 6.0 mg/dL, 6.5 mg/dL, 7.0 mg/dL,7.5 mg/dL, 8.0 mg/dL, 8.5 mg/dL, 9.0 mg/dL, 9.5 mg/dL, or 10.0 mg/dL).In some embodiments, demonstration of an elevated phosphate levelcomprises demonstrating an elevated phosphate level and at least one of:(i) a calcium-phosphate product of at least about 50 mg²/dL² and (ii) aserum creatinine level of grade 1 or greater. In some embodiments, anelevated phosphate level is demonstrated in comparison to an earliersample from the same subject (e.g., before administration of one or moredoses of a first FGFR1 inhibitor). In some embodiments, the first FGFR1inhibitor has a FGFR1 activity of less than about 500 nM in an in vitroFGFR1 kinase assay. In some embodiments, demonstration of a phosphatelevel that is not an elevated phosphate level occurs about 6 hours,about 12 hours, about 18 hours, about 1 day, about 1.5 days, about 2days, about 3 days, about 4 days, about 5 days, about 6 days, about 7days, about 8 days, about 9 days, about 10 days, about 2 weeks, about 3weeks, or about 4 weeks after administration of one or more doses of thecompound of Formula I. In some embodiments, a phosphate level that isnot an elevated phosphate level (e.g., in a blood sample) is a phosphatelevel of at between about 2.5 and about 4.5 mg/dL (e.g., between about2.5 and about 3.0 mg/dL, about 2.5 and about 3.5 mg/dL, about 2.5 andabout 4.0 mg/dL, about 3.0 to about 4.5 mg/dL, about 3.5 to about 4.5mg/dL, or about 4.0 to about 4.5 mg/dL). In some embodiments, aphosphate level that is not an elevated phosphate level (e.g., in ablood sample) is a phosphate level of at less than about 5 mg/dL (e.g.,less than about 4.5 mg/dL, 4.0 mg/dL, 3.5 mg/dL, or 3.0 mg/dL, or 2.5 mgd/L). In some embodiments, an additional therapy or therapeutic agent isnot an FGFR1 inhibitor.

In some embodiments, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting the fusion protein FGFR3-TACC3 in asample from the subject; and (b) administering to the subject atherapeutically effective amount of a first FGFR1 inhibitor. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a sample from a subject demonstrates an elevated phosphatelevel; and (d) administering a compound of Formula I or apharmaceutically acceptable salt or solvate thereof selected from thegroup consisting of a compound of Formula I selected from Examples 1-30,or a pharmaceutically acceptable salt or solvate thereof as amonotherapy or in conjunction with an additional therapy or therapeuticagent to the subject if the sample from the subject demonstrates anelevated phosphate level; or (e) administering additional doses of thefirst FGFR1 inhibitor of step (b) to the subject if the sample from thesubject does not demonstrate an elevated phosphate level. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a sample from a subject demonstrates an elevated phosphate leveland least one of: (i) a calcium-phosphate product of at least about 50mg²/dL² and (ii) a serum creatinine level of grade 1 or greater; and (d)administering a compound of Formula I or a pharmaceutically acceptablesalt or solvate thereof selected from the group consisting of a compoundof Formula I selected from Examples 1-30, or a pharmaceuticallyacceptable salt or solvate thereof as a monotherapy or in conjunctionwith an additional therapy or therapeutic agent to the subject if thesample from the subject demonstrates an elevated phosphate level andleast one of: (i) a calcium-phosphate product of at least about 50mg²/dL² and (ii) a serum creatinine level of grade 1 or greater; or (e)administering additional doses of the first FGFR1 inhibitor of step (b)to the subject if the sample from the subject does not demonstrate anelevated phosphate level and least one of: (i) a calcium-phosphateproduct of at least about 50 mg²/dL² and (ii) a serum creatinine levelof grade 1 or greater. In some embodiments, when the method comprisesadministering a compound of Formula I selected from Examples 1-30, themethod further comprises (f) determining that a sample from the subjectdoes not demonstrate an elevated phosphate level. In some embodiments,the FGFR1 inhibitor of step (b) is selected from the group consisting ofARQ-087, ASP5878, AZD4547, BGJ398, brivanib, Debio 1347, dovitinib,E7090, erdafitinib, HMPL-453, INCB054828, lenvatinib, lucitanib,MAX-40279, nintedanib, orantinib, pemigatinib, ponatinib, PRN1371,rogaratinib, sulfatinib, and TAS-120. In some embodiments, the sample ofstep (c) is a blood sample. In some embodiments of any of these methods,step (b) further includes administering to the subject a phosphatebinder. In some embodiments, step (c) occurs about 1 to about 12 days(e.g., about 1 day to about 2 days, about 1 day to about 3 days, about 1day to about 4 days, about 1 day to about 5 days, about 1 day to about 6days, about 1 day to about 7 days, about 1 day to about 8 days, about 1day to about 9 days, about 1 day to about 10 days, about 1 day to about11 days, about 2 days to about 12 days, about 3 days to about 12 days,about 4 days to about 12 days, about 5 days to about 12 days, about 6days to about 12 days, about 7 days to about 12 days, about 8 days toabout 12 days, about 9 days to about 12 days, about 10 days to about 12days, about 11 days to about 12 days, about 1 day, about 2 days, about 3days, about 4 days, about 5 days, about 6 days, about 7 days, about 8days, about 9 days, about 10 days, about 11 days, or about 12 days)after step (b). In some embodiments, an elevated phosphate level is aphosphate level (e.g., in a blood sample) of at least about 5 mg/dL(e.g., at least about 5.5 mg/dL, 6.0 mg/dL, 6.5 mg/dL, 7.0 mg/dL, 7.5mg/dL, 8.0 mg/dL, 8.5 mg/dL, 9.0 mg/dL, 9.5 mg/dL, or 10.0 mg/dL). Insome embodiments, demonstration of an elevated phosphate level comprisesdemonstrating an elevated phosphate level and at least one of: (i) acalcium-phosphate product of at least about 50 mg²/dL² and (ii) a serumcreatinine level of grade 1 or greater. In some embodiments, an elevatedphosphate level is demonstrated in comparison to an earlier sample fromthe same subject (e.g., before administration of one or more doses of afirst FGFR1 inhibitor). In some embodiments, the first FGFR1 inhibitorhas a FGFR1 activity of less than about 500 nM in an in vitro FGFR1kinase assay. In some embodiments, demonstration of a phosphate levelthat is not an elevated phosphate level occurs about 6 hours, about 12hours, about 18 hours, about 1 day, about 1.5 days, about 2 days, about3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8days, about 9 days, about 10 days, about 2 weeks, about 3 weeks, orabout 4 weeks after administration of one or more doses of the compoundof Formula I selected from Examples 1-30. In some embodiments, aphosphate level that is not an elevated phosphate level (e.g., in ablood sample) is a phosphate level of at between about 2.5 and about 4.5mg/dL (e.g., between about 2.5 and about 3.0 mg/dL, about 2.5 and about3.5 mg/dL, about 2.5 and about 4.0 mg/dL, about 3.0 to about 4.5 mg/dL,about 3.5 to about 4.5 mg/dL, or about 4.0 to about 4.5 mg/dL). In someembodiments, a phosphate level that is not an elevated phosphate level(e.g., in a blood sample) is a phosphate level of at less than about 5mg/dL (e.g., less than about 4.5 mg/dL, 4.0 mg/dL, 3.5 mg/dL, or 3.0mg/dL, or 2.5 mg d/L). In some embodiments, an additional therapy ortherapeutic agent is not an FGFR1 inhibitor.

For example, provided herein are methods for treating a FGFR-associatedcancer in a subject in need of such treatment, the method comprising (a)detecting a dysregulation of a FGFR gene, a FGFR kinase, or theexpression or activity or level of any of the same in a sample from thesubject; and (b) administering to the subject a therapeuticallyeffective amount of a first FGFR1 inhibitor. In some embodiments, themethods further comprise (after (b)) (c) determining whether a samplefrom a subject demonstrates an elevated phosphate level; and after aperiod of time, (d) administering a compound of Formula I, or apharmaceutically acceptable salt or solvate thereof as a monotherapy orin conjunction with an additional therapy or therapeutic agent to thesubject if the sample from the subject demonstrates an elevatedphosphate level; or (e) administering additional doses of the firstFGFR1 inhibitor of step (b) to the subject if the sample from thesubject does not demonstrate an elevated phosphate level. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a sample from a subject demonstrates an elevated phosphate leveland least one of: (i) a calcium-phosphate product of at least about 50mg²/dL² and (ii) a serum creatinine level of grade 1 or greater; andafter a period of time, (d) administering a compound of Formula I, or apharmaceutically acceptable salt or solvate thereof as a monotherapy orin conjunction with an additional therapy or therapeutic agent to thesubject if the sample from the subject demonstrates an elevatedphosphate level and least one of: (i) a calcium-phosphate product of atleast about 50 mg²/dL² and (ii) a serum creatinine level of grade 1 orgreater; or (e) administering additional doses of the first FGFR1inhibitor of step (b) to the subject if the sample from the subject doesnot demonstrate an elevated phosphate level and at least one of: (i) acalcium-phosphate product of at least about 50 mg²/dL² and (2) a serumcreatinine level of grade 1 or greater. In some embodiments, when themethod comprises administering a compound of Formula I, the methodfurther comprises (f) determining that a sample from the subject doesnot demonstrate an elevated phosphate level. In some embodiments, theFGFR1 inhibitor of step (b) is selected from the group consisting ofARQ-087, ASP5878, AZD4547, BGJ398, brivanib, Debio 1347, dovitinib,E7090, erdafitinib, HMPL-453, INCB054828, lenvatinib, lucitanib,MAX-40279, nintedanib, orantinib, pemigatinib, ponatinib, PRN1371,rogaratinib, suffatinib, and TAS-120. In some embodiments, the sample ofstep (c) is a blood sample. In some embodiments of any of these methods,step (b) further includes administering to the subject a phosphatebinder. In some embodiments, step (c) occurs about 1 to about 12 days(e.g., about 1 day to about 2 days, about 1 day to about 3 days, about 1day to about 4 days, about 1 day to about 5 days, about 1 day to about 6days, about 1 day to about 7 days, about 1 day to about 8 days, about 1day to about 9 days, about 1 day to about 10 days, about 1 day to about11 days, about 2 days to about 12 days, about 3 days to about 12 days,about 4 days to about 12 days, about 5 days to about 12 days, about 6days to about 12 days, about 7 days to about 12 days, about 8 days toabout 12 days, about 9 days to about 12 days, about 10 days to about 12days, about 11 days to about 12 days, about 1 day, about 2 days, about 3days, about 4 days, about 5 days, about 6 days, about 7 days, about 8days, about 9 days, about 10 days, about 11 days, or about 12 days)after step (b). In some embodiments, the period of time between step (c)and step (d) is about 1 day, about 1.5 days, about 2 days, about 3 days,about 4 days, about 5 days, about 6 days, about 7 days, about 8 days,about 9 days, about 10 days, about 2 weeks, about 3 weeks, about 1month, about 2 months, about 3 months, about 4 months, about 5 months,about 6 months, about 7 months, about 8 months, about 9 months, about 10months, about 11 months, about 1 year, about 1.5 years, about 2 years,about 3 years, about 4 years, about 5 years, about 6 years, about 7years, about 8 years, about 9 years, about 10 years, about 12 years,about 14 years, about 16 years, about 18 years, about 20 years, about 22years, about 24 years, about 26 years, about 28 years, about 30 years,about 35 years, about 40 years, or about 50 years. In some embodiments,an elevated phosphate level is a phosphate level (e.g., in a bloodsample) of at least about 5 mg/dL (e.g., at least about 5.5 mg/dL, 6.0mg/dL, 6.5 mg/dL, 7.0 mg/dL, 7.5 mg/dL, 8.0 mg/dL, 8.5 mg/dL, 9.0 mg/dL,9.5 mg/dL, or 10.0 mg/dL). In some embodiments, demonstration of anelevated phosphate level comprises demonstrating an elevated phosphatelevel and at least one of: (i) a calcium-phosphate product of at leastabout 50 mg²/dL² and (ii) a serum creatinine level of grade 1 orgreater. In some embodiments, an elevated phosphate level isdemonstrated in comparison to an earlier sample from the same subject(e.g., before administration of one or more doses of a first FGFR1inhibitor). In some embodiments, the first FGFR1 inhibitor has a FGFR1activity of less than about 500 nM in an in vitro FGFR1 kinase assay. Insome embodiments, demonstration of a phosphate level that is not anelevated phosphate level occurs about 6 hours, about 12 hours, about 18hours, about 1 day, about 1.5 days, about 2 days, about 3 days, about 4days, about 5 days, about 6 days, about 7 days, about 8 days, about 9days, about 10 days, about 2 weeks, about 3 weeks, or about 4 weeksafter administration of one or more doses of the compound of Formula I.In some embodiments, a phosphate level that is not an elevated phosphatelevel (e.g., in a blood sample) is a phosphate level of at between about2.5 and about 4.5 mg/dL (e.g., between about 2.5 and about 3.0 mg/dL,about 2.5 and about 3.5 mg/dL, about 2.5 and about 4.0 mg/dL, about 3.0to about 4.5 mg/dL, about 3.5 to about 4.5 mg/dL, or about 4.0 to about4.5 mg/dL). In some embodiments, a phosphate level that is not anelevated phosphate level (e.g., in a blood sample) is a phosphate levelof at less than about 5 mg/dL (e.g., less than about 4.5 mg/dL, 4.0mg/dL, 3.5 mg/dL, or 3.0 mg/dL, or 2.5 mg d/L). In some embodiments, anadditional therapy or therapeutic agent is not an FGFR1 inhibitor.

For example, provided herein are methods for treating a FGFR-associatedcancer in a subject in need of such treatment, the method comprising (a)detecting a dysregulation of a FGFR gene, a FGFR kinase, or theexpression or activity or level of any of the same in a sample from thesubject; and (b) administering to the subject a therapeuticallyeffective amount of a first FGFR1 inhibitor. In some embodiments, themethods further comprise (after (b)) (c) determining whether a samplefrom a subject demonstrates an elevated phosphate level; and after aperiod of time, (d) administering a compound of Formula I selected fromExamples 1-30, or a pharmaceutically acceptable salt or solvate thereofas a monotherapy or in conjunction with an additional therapy ortherapeutic agent to the subject if the sample from the subjectdemonstrates an elevated phosphate level; or (e) administeringadditional doses of the first FGFR1 inhibitor of step (b) to the subjectif the sample from the subject does not demonstrate an elevatedphosphate level. In some embodiments, the methods further comprise(after (b)) (c) determining whether a sample from a subject demonstratesan elevated phosphate level and least one of: (i) a calcium-phosphateproduct of at least about 50 mg²/dL² and (ii) a serum creatinine levelof grade 1 or greater; and after a period of time, (d) administering acompound of Formula I selected from Examples 1-30, or a pharmaceuticallyacceptable salt or solvate thereof as a monotherapy or in conjunctionwith an additional therapy or therapeutic agent to the subject if thesample from the subject demonstrates an elevated phosphate level andleast one of: (i) a calcium-phosphate product of at least about 50mg²/dL² and (ii) a serum creatinine level of grade 1 or greater; or (e)administering additional doses of the first FGFR1 inhibitor of step (b)to the subject if the sample from the subject does not demonstrate anelevated phosphate level and at least one of: (i) a calcium-phosphateproduct of at least about 50 mg²/dL² and (2) a serum creatinine level ofgrade 1 or greater. In some embodiments, when the method comprisesadministering a compound of Formula I selected from Examples 1-30, themethod further comprises (f) determining that a sample from the subjectdoes not demonstrate an elevated phosphate level. In some embodiments,the FGFR1 inhibitor of step (b) is selected from the group consisting ofARQ-087, ASP5878, AZD4547, BGJ398, brivanib, Debio 1347, dovitinib,E7090, erdafitinib, HMPL-453, INCB054828, lenvatinib, lucitanib,MAX-40279, nintedanib, orantinib, pemigatinib, ponatinib, PRN1371,rogaratinib, sulfatinib, and TAS-120. In some embodiments, the sample ofstep (c) is a blood sample. In some embodiments of any of these methods,step (b) further includes administering to the subject a phosphatebinder. In some embodiments, step (c) occurs about 1 to about 12 days(e.g., about 1 day to about 2 days, about 1 day to about 3 days, about 1day to about 4 days, about 1 day to about 5 days, about 1 day to about 6days, about 1 day to about 7 days, about 1 day to about 8 days, about 1day to about 9 days, about 1 day to about 10 days, about 1 day to about11 days, about 2 days to about 12 days, about 3 days to about 12 days,about 4 days to about 12 days, about 5 days to about 12 days, about 6days to about 12 days, about 7 days to about 12 days, about 8 days toabout 12 days, about 9 days to about 12 days, about 10 days to about 12days, about 11 days to about 12 days, about 1 day, about 2 days, about 3days, about 4 days, about 5 days, about 6 days, about 7 days, about 8days, about 9 days, about 10 days, about 11 days, or about 12 days)after step (b). In some embodiments, the period of time between step (c)and step (d) is about 1 day, about 1.5 days, about 2 days, about 3 days,about 4 days, about 5 days, about 6 days, about 7 days, about 8 days,about 9 days, about 10 days, about 2 weeks, about 3 weeks, about 1month, about 2 months, about 3 months, about 4 months, about 5 months,about 6 months, about 7 months, about 8 months, about 9 months, about 10months, about 11 months, about 1 year, about 1.5 years, about 2 years,about 3 years, about 4 years, about 5 years, about 6 years, about 7years, about 8 years, about 9 years, about 10 years, about 12 years,about 14 years, about 16 years, about 18 years, about 20 years, about 22years, about 24 years, about 26 years, about 28 years, about 30 years,about 35 years, about 40 years, or about 50 years. In some embodiments,an elevated phosphate level is a phosphate level (e.g., in a bloodsample) of at least about 5 mg/dL (e.g., at least about 5.5 mg/dL, 6.0mg/dL, 6.5 mg/dL, 7.0 mg/dL, 7.5 mg/dL, 8.0 mg/dL, 8.5 mg/dL, 9.0 mg/dL,9.5 mg/dL, or 10.0 mg/dL). In some embodiments, demonstration of anelevated phosphate level comprises demonstrating an elevated phosphatelevel and at least one of: (i) a calcium-phosphate product of at leastabout 50 mg²/dL² and (ii) a serum creatinine level of grade 1 orgreater. In some embodiments, an elevated phosphate level isdemonstrated in comparison to an earlier sample from the same subject(e.g., before administration of one or more doses of a first FGFR1inhibitor). In some embodiments, the first FGFR1 inhibitor has a FGFR1activity of less than about 500 nM in an in vitro FGFR1 kinase assay. Insome embodiments, demonstration of a phosphate level that is not anelevated phosphate level occurs about 6 hours, about 12 hours, about 18hours, about 1 day, about 1.5 days, about 2 days, about 3 days, about 4days, about 5 days, about 6 days, about 7 days, about 8 days, about 9days, about 10 days, about 2 weeks, about 3 weeks, or about 4 weeksafter administration of one or more doses of the compound of Formula Iselected from Examples 1-30. In some embodiments, a phosphate level thatis not an elevated phosphate level (e.g., in a blood sample) is aphosphate level of at between about 2.5 and about 4.5 mg/dL (e.g.,between about 2.5 and about 3.0 mg/dL, about 2.5 and about 3.5 mg/dL,about 2.5 and about 4.0 mg/dL, about 3.0 to about 4.5 mg/dL, about 3.5to about 4.5 mg/dL, or about 4.0 to about 4.5 mg/dL). In someembodiments, a phosphate level that is not an elevated phosphate level(e.g., in a blood sample) is a phosphate level of at less than about 5mg/dL (e.g., less than about 4.5 mg/dL, 4.0 mg/dL, 3.5 mg/dL, or 3.0mg/dL, or 2.5 mg d/L). In some embodiments, an additional therapy ortherapeutic agent is not an FGFR1 inhibitor.

In some embodiments, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting one or more fusion proteins of Table BAand/or one or more FGFR kinase protein pointmutations/insertions/deletions of Table BC in a sample from the subject;and (b) administering to the subject a therapeutically effective amountof a first FGFR1 inhibitor. In some embodiments, the methods furthercomprise (after (b)) (c) determining whether a sample from a subjectdemonstrates an elevated phosphate level; and after a period of time,(d) administering a compound of Formula I, or a pharmaceuticallyacceptable salt or solvate thereof as a monotherapy or in conjunctionwith an additional therapy or therapeutic agent to the subject if thesample from the subject demonstrates an elevated phosphate level; or (e)administering additional doses of the first FGFR1 inhibitor of step (b)to the subject if the sample from the subject does not demonstrate anelevated phosphate level. In some embodiments, the methods furthercomprise (after (b)) (c) determining whether a sample from a subjectdemonstrates an elevated phosphate level and least one of: (i) acalcium-phosphate product of at least about 50 mg²/dL² and (ii) a serumcreatinine level of grade 1 or greater; and after a period of time, (d)administering a compound of Formula I, or a pharmaceutically acceptablesalt or solvate thereof as a monotherapy or in conjunction with anadditional therapy or therapeutic agent to the subject if the samplefrom the subject demonstrates an elevated phosphate level and least oneof: (i) a calcium-phosphate product of at least about 50 mg²/dL² and(ii) a serum creatinine level of grade 1 or greater; or (e)administering additional doses of the first FGFR1 inhibitor of step (b)to the subject if the sample from the subject does not demonstrate anelevated phosphate level and least one of: (i) a calcium-phosphateproduct of at least about 50 mg²/dL² and (ii) a serum creatinine levelof grade 1 or greater. In some embodiments, when the method comprisesadministering a compound of Formula I, the method further comprises (f)determining that a sample from the subject does not demonstrate anelevated phosphate level. In some embodiments, the FGFR1 inhibitor ofstep (b) is selected from the group consisting of ARQ-087, ASP5878,AZD4547, BGJ398, brivanib, Debio 1347, dovitinib, E7090, erdafitinib,HMPL-453, INCB054828, lenvatinib, lucitanib, MAX-40279, nintedanib,orantinib, pemigatinib, ponatinib, PRN1371, rogaratinib, sulfatinib, andTAS-120. In some embodiments, the sample of step (c) is a blood sample.In some embodiments of any of these methods, step (b) further includesadministering to the subject a phosphate binder. In some embodiments,step (c) occurs about 1 to about 12 days (e.g., about 1 day to about 2days, about 1 day to about 3 days, about 1 day to about 4 days, about 1day to about 5 days, about 1 day to about 6 days, about 1 day to about 7days, about 1 day to about 8 days, about 1 day to about 9 days, about 1day to about 10 days, about 1 day to about 11 days, about 2 days toabout 12 days, about 3 days to about 12 days, about 4 days to about 12days, about 5 days to about 12 days, about 6 days to about 12 days,about 7 days to about 12 days, about 8 days to about 12 days, about 9days to about 12 days, about 10 days to about 12 days, about 11 days toabout 12 days, about 1 day, about 2 days, about 3 days, about 4 days,about 5 days, about 6 days, about 7 days, about 8 days, about 9 days,about 10 days, about 11 days, or about 12 days) after step (b). In someembodiments, the period of time between step (c) and step (d) is about 1day, about 1.5 days, about 2 days, about 3 days, about 4 days, about 5days, about 6 days, about 7 days, about 8 days, about 9 days, about 10days, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about3 months, about 4 months, about 5 months, about 6 months, about 7months, about 8 months, about 9 months, about 10 months, about 11months, about 1 year, about 1.5 years, about 2 years, about 3 years,about 4 years, about 5 years, about 6 years, about 7 years, about 8years, about 9 years, about 10 years, about 12 years, about 14 years,about 16 years, about 18 years, about 20 years, about 22 years, about 24years, about 26 years, about 28 years, about 30 years, about 35 years,about 40 years, or about 50 years. In some embodiments, an elevatedphosphate level is a phosphate level (e.g., in a blood sample) of atleast about 5 mg/dL (e.g., at least about 5.5 mg/dL, 6.0 mg/dL, 6.5mg/dL, 7.0 mg/dL, 7.5 mg/dL, 8.0 mg/dL, 8.5 mg/dL, 9.0 mg/dL, 9.5 mg/dL,or 10.0 mg/dL). In some embodiments, demonstration of an elevatedphosphate level comprises demonstrating an elevated phosphate level andat least one of: (i) a calcium-phosphate product of at least about 50mg²/dL² and (ii) a serum creatinine level of grade 1 or greater. In someembodiments, an elevated phosphate level is demonstrated in comparisonto an earlier sample from the same subject (e.g., before administrationof one or more doses of a first FGFR1 inhibitor). In some embodiments,the first FGFR1 inhibitor has a FGFR1 activity of less than about 500 nMin an in vitro FGFR1 kinase assay. In some embodiments, demonstration ofa phosphate level that is not an elevated phosphate level occurs about 6hours, about 12 hours, about 18 hours, about 1 day, about 1.5 days,about 2 days, about 3 days, about 4 days, about 5 days, about 6 days,about 7 days, about 8 days, about 9 days, about 10 days, about 2 weeks,about 3 weeks, or about 4 weeks after administration of one or moredoses of the compound of Formula I. In some embodiments, a phosphatelevel that is not an elevated phosphate level (e.g., in a blood sample)is a phosphate level of at between about 2.5 and about 4.5 mg/dL (e.g.,between about 2.5 and about 3.0 mg/dL, about 2.5 and about 3.5 mg/dL,about 2.5 and about 4.0 mg/dL, about 3.0 to about 4.5 mg/dL, about 3.5to about 4.5 mg/dL, or about 4.0 to about 4.5 mg/dL). In someembodiments, a phosphate level that is not an elevated phosphate level(e.g., in a blood sample) is a phosphate level of at less than about 5mg/dL (e.g., less than about 4.5 mg/dL, 4.0 mg/dL, 3.5 mg/dL, or 3.0mg/dL, or 2.5 mg d/L). In some embodiments, an additional therapy ortherapeutic agent is not an FGFR1 inhibitor.

In some embodiments, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting one or more fusion proteins of Table BAand/or one or more FGFR kinase protein pointmutations/insertions/deletions of Table BC in a sample from the subject;and (b) administering to the subject a therapeutically effective amountof a first FGFR1 inhibitor. In some embodiments, the methods furthercomprise (after (b)) (c) determining whether a sample from a subjectdemonstrates an elevated phosphate level; and after a period of time,(d) administering a compound of Formula I selected from Examples 1-30,or a pharmaceutically acceptable salt or solvate thereof as amonotherapy or in conjunction with an additional therapy or therapeuticagent to the subject if the sample from the subject demonstrates anelevated phosphate level; or (e) administering additional doses of thefirst FGFR1 inhibitor of step (b) to the subject if the sample from thesubject does not demonstrate an elevated phosphate level. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a sample from a subject demonstrates an elevated phosphate leveland least one of: (i) a calcium-phosphate product of at least about 50mg²/dL² and (ii) a serum creatinine level of grade 1 or greater; andafter a period of time, (d) administering a compound of Formula Iselected from Examples 1-30, or a pharmaceutically acceptable salt orsolvate thereof as a monotherapy or in conjunction with an additionaltherapy or therapeutic agent to the subject if the sample from thesubject demonstrates an elevated phosphate level and least one of: (i) acalcium-phosphate product of at least about 50 mg²/dL² and (ii) a serumcreatinine level of grade 1 or greater; or (e) administering additionaldoses of the first FGFR1 inhibitor of step (b) to the subject if thesample from the subject does not demonstrate an elevated phosphate leveland least one of: (i) a calcium-phosphate product of at least about 50mg²/dL² and (ii) a serum creatinine level of grade 1 or greater. In someembodiments, when the method comprises administering a compound ofFormula I selected from Examples 1-30, the method further comprises (f)determining that a sample from the subject does not demonstrate anelevated phosphate level. In some embodiments, the FGFR1 inhibitor ofstep (b) is selected from the group consisting of ARQ-087, ASP5878,AZD4547, BGJ398, brivanib, Debio 1347, dovitinib, E7090, erdafitinib,HMPL-453, INCB054828, lenvatinib, lucitanib, MAX-40279, nintedanib,orantinib, pemigatinib, ponatinib, PRN1371, rogaratinib, sulfatinib, andTAS-120. In some embodiments, the sample of step (c) is a blood sample.In some embodiments of any of these methods, step (b) further includesadministering to the subject a phosphate binder. In some embodiments,step (c) occurs about 1 to about 12 days (e.g., about 1 day to about 2days, about 1 day to about 3 days, about 1 day to about 4 days, about 1day to about 5 days, about 1 day to about 6 days, about 1 day to about 7days, about 1 day to about 8 days, about 1 day to about 9 days, about 1day to about 10 days, about 1 day to about 11 days, about 2 days toabout 12 days, about 3 days to about 12 days, about 4 days to about 12days, about 5 days to about 12 days, about 6 days to about 12 days,about 7 days to about 12 days, about 8 days to about 12 days, about 9days to about 12 days, about 10 days to about 12 days, about 11 days toabout 12 days, about 1 day, about 2 days, about 3 days, about 4 days,about 5 days, about 6 days, about 7 days, about 8 days, about 9 days,about 10 days, about 11 days, or about 12 days) after step (b). In someembodiments, the period of time between step (c) and step (d) is about 1day, about 1.5 days, about 2 days, about 3 days, about 4 days, about 5days, about 6 days, about 7 days, about 8 days, about 9 days, about 10days, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about3 months, about 4 months, about 5 months, about 6 months, about 7months, about 8 months, about 9 months, about 10 months, about 11months, about 1 year, about 1.5 years, about 2 years, about 3 years,about 4 years, about 5 years, about 6 years, about 7 years, about 8years, about 9 years, about 10 years, about 12 years, about 14 years,about 16 years, about 18 years, about 20 years, about 22 years, about 24years, about 26 years, about 28 years, about 30 years, about 35 years,about 40 years, or about 50 years. In some embodiments, an elevatedphosphate level is a phosphate level (e.g., in a blood sample) of atleast about 5 mg/dL (e.g., at least about 5.5 mg/dL, 6.0 mg/dL, 6.5mg/dL, 7.0 mg/dL, 7.5 mg/dL, 8.0 mg/dL, 8.5 mg/dL, 9.0 mg/dL, 9.5 mg/dL,or 10.0 mg/dL). In some embodiments, demonstration of an elevatedphosphate level comprises demonstrating an elevated phosphate level andat least one of: (i) a calcium-phosphate product of at least about 50mg²/dL² and (ii) a serum creatinine level of grade 1 or greater. In someembodiments, an elevated phosphate level is demonstrated in comparisonto an earlier sample from the same subject (e.g., before administrationof one or more doses of a first FGFR1 inhibitor). In some embodiments,the first FGFR1 inhibitor has a FGFR1 activity of less than about 500 nMin an in vitro FGFR1 kinase assay. In some embodiments, demonstration ofa phosphate level that is not an elevated phosphate level occurs about 6hours, about 12 hours, about 18 hours, about 1 day, about 1.5 days,about 2 days, about 3 days, about 4 days, about 5 days, about 6 days,about 7 days, about 8 days, about 9 days, about 10 days, about 2 weeks,about 3 weeks, or about 4 weeks after administration of one or moredoses of the compound of Formula I selected from Examples 1-30. In someembodiments, a phosphate level that is not an elevated phosphate level(e.g., in a blood sample) is a phosphate level of at between about 2.5and about 4.5 mg/dL (e.g., between about 2.5 and about 3.0 mg/dL, about2.5 and about 3.5 mg/dL, about 2.5 and about 4.0 mg/dL, about 3.0 toabout 4.5 mg/dL, about 3.5 to about 4.5 mg/dL, or about 4.0 to about 4.5mg/dL). In some embodiments, a phosphate level that is not an elevatedphosphate level (e.g., in a blood sample) is a phosphate level of atless than about 5 mg/dL (e.g., less than about 4.5 mg/dL, 4.0 mg/dL, 3.5mg/dL, or 3.0 mg/dL, or 2.5 mg d/L). In some embodiments, an additionaltherapy or therapeutic agent is not an FGFR1 inhibitor.

In some embodiments, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting the fusion protein FGFR3-TACC3 in asample from the subject; and (b) administering to the subject atherapeutically effective amount of a first FGFR1 inhibitor. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a sample from a subject demonstrates an elevated phosphatelevel; and after a period of time, (d) administering a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereofselected from the group consisting of a compound of Formula I, or apharmaceutically acceptable salt or solvate thereof as a monotherapy orin conjunction with an additional therapy or therapeutic agent to thesubject if the sample from the subject demonstrates an elevatedphosphate level; or (e) administering additional doses of the firstFGFR1 inhibitor of step (b) to the subject if the sample from thesubject does not demonstrate an elevated phosphate level. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a sample from a subject demonstrates an elevated phosphate leveland least one of: (i) a calcium-phosphate product of at least about 50mg²/dL² and (ii) a serum creatinine level of grade 1 or greater; andafter a period of time, (d) administering a compound of Formula I or apharmaceutically acceptable salt or solvate thereof selected from thegroup consisting of a compound of Formula I, or a pharmaceuticallyacceptable salt or solvate thereof as a monotherapy or in conjunctionwith an additional therapy or therapeutic agent to the subject if thesample from the subject demonstrates an elevated phosphate level andleast one of: (i) a calcium-phosphate product of at least about 50mg²/dL² and (ii) a serum creatinine level of grade 1 or greater; or (e)administering additional doses of the first FGFR1 inhibitor of step (b)to the subject if the sample from the subject does not demonstrate anelevated phosphate level and least one of: (i) a calcium-phosphateproduct of at least about 50 mg²/dL² and (ii) a serum creatinine levelof grade 1 or greater. In some embodiments, when the method comprisesadministering a compound of Formula I, the method further comprises (f)determining that a sample from the subject does not demonstrate anelevated phosphate level. In some embodiments, the FGFR1 inhibitor ofstep (b) is selected from the group consisting of ARQ-087, ASP5878,AZD4547, BGJ398, brivanib, Debio 1347, dovitinib, E7090, erdafitinib,HMPL-453, INCB054828, lenvatinib, lucitanib, MAX-40279, nintedanib,orantinib, pemigatinib, ponatinib, PRN1371, rogaratinib, sulfatinib, andTAS-120. In some embodiments, the sample of step (c) is a blood sample.In some embodiments of any of these methods, step (b) further includesadministering to the subject a phosphate binder. In some embodiments,step (c) occurs about 1 to about 12 days (e.g., about 1 day to about 2days, about 1 day to about 3 days, about 1 day to about 4 days, about 1day to about 5 days, about 1 day to about 6 days, about 1 day to about 7days, about 1 day to about 8 days, about 1 day to about 9 days, about 1day to about 10 days, about 1 day to about 11 days, about 2 days toabout 12 days, about 3 days to about 12 days, about 4 days to about 12days, about 5 days to about 12 days, about 6 days to about 12 days,about 7 days to about 12 days, about 8 days to about 12 days, about 9days to about 12 days, about 10 days to about 12 days, about 11 days toabout 12 days, about 1 day, about 2 days, about 3 days, about 4 days,about 5 days, about 6 days, about 7 days, about 8 days, about 9 days,about 10 days, about 11 days, or about 12 days) after step (b). In someembodiments, the period of time between step (c) and step (d) is about 1day, about 1.5 days, about 2 days, about 3 days, about 4 days, about 5days, about 6 days, about 7 days, about 8 days, about 9 days, about 10days, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about3 months, about 4 months, about 5 months, about 6 months, about 7months, about 8 months, about 9 months, about 10 months, about 11months, about 1 year, about 1.5 years, about 2 years, about 3 years,about 4 years, about 5 years, about 6 years, about 7 years, about 8years, about 9 years, about 10 years, about 12 years, about 14 years,about 16 years, about 18 years, about 20 years, about 22 years, about 24years, about 26 years, about 28 years, about 30 years, about 35 years,about 40 years, or about 50 years. In some embodiments, an elevatedphosphate level is a phosphate level (e.g., in a blood sample) of atleast about 5 mg/dL (e.g., at least about 5.5 mg/dL, 6.0 mg/dL, 6.5mg/dL, 7.0 mg/dL, 7.5 mg/dL, 8.0 mg/dL, 8.5 mg/dL, 9.0 mg/dL, 9.5 mg/dL,or 10.0 mg/dL). In some embodiments, demonstration of an elevatedphosphate level comprises demonstrating an elevated phosphate level andat least one of: (i) a calcium-phosphate product of at least about 50mg²/dL² and (ii) a serum creatinine level of grade 1 or greater. In someembodiments, an elevated phosphate level is demonstrated in comparisonto an earlier sample from the same subject (e.g., before administrationof one or more doses of a first FGFR1 inhibitor). In some embodiments,the first FGFR1 inhibitor has a FGFR1 activity of less than about 500 nMin an in vitro FGFR1 kinase assay. In some embodiments, demonstration ofa phosphate level that is not an elevated phosphate level occurs about 6hours, about 12 hours, about 18 hours, about 1 day, about 1.5 days,about 2 days, about 3 days, about 4 days, about 5 days, about 6 days,about 7 days, about 8 days, about 9 days, about 10 days, about 2 weeks,about 3 weeks, or about 4 weeks after administration of one or moredoses of the compound of Formula I. In some embodiments, a phosphatelevel that is not an elevated phosphate level (e.g., in a blood sample)is a phosphate level of at between about 2.5 and about 4.5 mg/dL (e.g.,between about 2.5 and about 3.0 mg/dL, about 2.5 and about 3.5 mg/dL,about 2.5 and about 4.0 mg/dL, about 3.0 to about 4.5 mg/dL, about 3.5to about 4.5 mg/dL, or about 4.0 to about 4.5 mg/dL). In someembodiments, a phosphate level that is not an elevated phosphate level(e.g., in a blood sample) is a phosphate level of at less than about 5mg/dL (e.g., less than about 4.5 mg/dL, 4.0 mg/dL, 3.5 mg/dL, or 3.0mg/dL, or 2.5 mg d/L). In some embodiments, an additional therapy ortherapeutic agent is not an FGFR1 inhibitor.

In some embodiments, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting the fusion protein FGFR3-TACC3 in asample from the subject; and (b) administering to the subject atherapeutically effective amount of a first FGFR1 inhibitor. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a sample from a subject demonstrates an elevated phosphatelevel; and after a period of time, (d) administering a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereofselected from the group consisting of a compound of Formula I selectedfrom Examples 1-30, or a pharmaceutically acceptable salt or solvatethereof as a monotherapy or in conjunction with an additional therapy ortherapeutic agent to the subject if the sample from the subjectdemonstrates an elevated phosphate level; or (e) administeringadditional doses of the first FGFR1 inhibitor of step (b) to the subjectif the sample from the subject does not demonstrate an elevatedphosphate level. In some embodiments, the methods further comprise(after (b)) (c) determining whether a sample from a subject demonstratesan elevated phosphate level and least one of: (i) a calcium-phosphateproduct of at least about 50 mg²/dL² and (ii) a serum creatinine levelof grade 1 or greater; and after a period of time, (d) administering acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof selected from the group consisting of a compound of Formula Iselected from Examples 1-30, or a pharmaceutically acceptable salt orsolvate thereof as a monotherapy or in conjunction with an additionaltherapy or therapeutic agent to the subject if the sample from thesubject demonstrates an elevated phosphate level and least one of: (i) acalcium-phosphate product of at least about 50 mg²/dL² and (ii) a serumcreatinine level of grade 1 or greater; or (e) administering additionaldoses of the first FGFR1 inhibitor of step (b) to the subject if thesample from the subject does not demonstrate an elevated phosphate leveland least one of: (i) a calcium-phosphate product of at least about 50mg²/dL² and (ii) a serum creatinine level of grade 1 or greater. In someembodiments, when the method comprises administering a compound ofFormula I selected from Examples 1-30, the method further comprises (f)determining that a sample from the subject does not demonstrate anelevated phosphate level. In some embodiments, the FGFR1 inhibitor ofstep (b) is selected from the group consisting of ARQ-087, ASP5878,AZD4547, BGJ398, brivanib, Debio 1347, dovitinib, E7090, erdafitinib,HMPL-453, INCB054828, lenvatinib, lucitanib, MAX-40279, nintedanib,orantinib, pemigatinib, ponatinib, PRN1371, rogaratinib, sulfatinib, andTAS-120. In some embodiments, the sample of step (c) is a blood sample.In some embodiments of any of these methods, step (b) further includesadministering to the subject a phosphate binder. In some embodiments,step (c) occurs about 1 to about 12 days (e.g., about 1 day to about 2days, about 1 day to about 3 days, about 1 day to about 4 days, about 1day to about 5 days, about 1 day to about 6 days, about 1 day to about 7days, about 1 day to about 8 days, about 1 day to about 9 days, about 1day to about 10 days, about 1 day to about 11 days, about 2 days toabout 12 days, about 3 days to about 12 days, about 4 days to about 12days, about 5 days to about 12 days, about 6 days to about 12 days,about 7 days to about 12 days, about 8 days to about 12 days, about 9days to about 12 days, about 10 days to about 12 days, about 11 days toabout 12 days, about 1 day, about 2 days, about 3 days, about 4 days,about 5 days, about 6 days, about 7 days, about 8 days, about 9 days,about 10 days, about 11 days, or about 12 days) after step (b). In someembodiments, the period of time between step (c) and step (d) is about 1day, about 1.5 days, about 2 days, about 3 days, about 4 days, about 5days, about 6 days, about 7 days, about 8 days, about 9 days, about 10days, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about3 months, about 4 months, about 5 months, about 6 months, about 7months, about 8 months, about 9 months, about 10 months, about 11months, about 1 year, about 1.5 years, about 2 years, about 3 years,about 4 years, about 5 years, about 6 years, about 7 years, about 8years, about 9 years, about 10 years, about 12 years, about 14 years,about 16 years, about 18 years, about 20 years, about 22 years, about 24years, about 26 years, about 28 years, about 30 years, about 35 years,about 40 years, or about 50 years. In some embodiments, an elevatedphosphate level is a phosphate level (e.g., in a blood sample) of atleast about 5 mg/dL (e.g., at least about 5.5 mg/dL, 6.0 mg/dL, 6.5mg/dL, 7.0 mg/dL, 7.5 mg/dL, 8.0 mg/dL, 8.5 mg/dL, 9.0 mg/dL, 9.5 mg/dL,or 10.0 mg/dL). In some embodiments, demonstration of an elevatedphosphate level comprises demonstrating an elevated phosphate level andat least one of: (i) a calcium-phosphate product of at least about 50mg²/dL² and (ii) a serum creatinine level of grade 1 or greater. In someembodiments, an elevated phosphate level is demonstrated in comparisonto an earlier sample from the same subject (e.g., before administrationof one or more doses of a first FGFR1 inhibitor). In some embodiments,the first FGFR1 inhibitor has a FGFR1 activity of less than about 500 nMin an in vitro FGFR1 kinase assay. In some embodiments, demonstration ofa phosphate level that is not an elevated phosphate level occurs about 6hours, about 12 hours, about 18 hours, about 1 day, about 1.5 days,about 2 days, about 3 days, about 4 days, about 5 days, about 6 days,about 7 days, about 8 days, about 9 days, about 10 days, about 2 weeks,about 3 weeks, or about 4 weeks after administration of one or moredoses of the compound of Formula I selected from Examples 1-30. In someembodiments, a phosphate level that is not an elevated phosphate level(e.g., in a blood sample) is a phosphate level of at between about 2.5and about 4.5 mg/dL (e.g., between about 2.5 and about 3.0 mg/dL, about2.5 and about 3.5 mg/dL, about 2.5 and about 4.0 mg/dL, about 3.0 toabout 4.5 mg/dL, about 3.5 to about 4.5 mg/dL, or about 4.0 to about 4.5mg/dL). In some embodiments, a phosphate level that is not an elevatedphosphate level (e.g., in a blood sample) is a phosphate level of atless than about 5 mg/dL (e.g., less than about 4.5 mg/dL, 4.0 mg/dL, 3.5mg/dL, or 3.0 mg/dL, or 2.5 mg d/L). In some embodiments, an additionaltherapy or therapeutic agent is not an FGFR1 inhibitor.

For example, provided herein are methods of treating a subject having acancer that include: identifying a subject having a FGFR-associatedcancer (e.g., any of the FGFR-associated cancers described herein orknown in the art) and previously demonstrating an elevated phosphatelevel; and administering to the identified subject a compound of FormulaI or a pharmaceutically acceptable salt or solvate thereof. In someembodiments, following administration of a compound of Formula I, themethods further comprise determining that a sample from the subject doesnot demonstrate an elevated phosphate level. In some embodiments,demonstration of an elevated phosphate level occurs about 1 day to about12 days (e.g., about 1 day to about 2 days, about 1 day to about 3 daysabout 1 day to about 4 days, about 1 day to about 5 days, about 1 day toabout 6 days, about 1 day to about 7 days, about 1 day to about 8 days,about 1 day to about 9 days, about 1 day to about 10 days, about 1 dayto about 11 days, about 2 days to about 12 days, about 3 days to about12 days, about 4 days to about 12 days, about 5 days to about 12 days,about 6 days to about 12 days, about 7 days to about 12 days, about 8days to about 12 days, about 9 days to about 12 days, about 10 days toabout 12 days, about 11 days to about 12 days, about 1 day, about 2days, about 3 days, about 4 days, about 5 days, about 6 days, about 7days, about 8 days, about 9 days, about 10 days, about 11 days, or about12 days) following administration of one or more doses of a first FGFRinhibitor. In some embodiments, an elevated phosphate level is aphosphate level (e.g., in a blood sample) of at least about 5 mg/dL(e.g., at least about 5.5 mg/dL, 6.0 mg/dL, 6.5 mg/dL, 7.0 mg/dL, 7.5mg/dL, 8.0 mg/dL, 8.5 mg/dL, 9.0 mg/dL, 9.5 mg/dL, or 10.0 mg/dL). Insome embodiments, demonstration of an elevated phosphate level comprisesdemonstrating an elevated phosphate level and at least one of: (i) acalcium-phosphate product of at least about 50 mg²/dL² and (ii) a serumcreatinine level of grade 1 or greater. In some embodiments, an elevatedphosphate level is demonstrated in comparison to an earlier sample fromthe same subject (e.g., before administration of one or more doses of afirst FGFR1 inhibitor). In some embodiments, the first FGFR1 inhibitorhas a FGFR1 activity of less than about 500 nM in an in vitro FGFR1kinase assay. In some embodiments, demonstration of a phosphate levelthat is not an elevated phosphate level occurs about 6 hours, about 12hours, about 18 hours, about 1 day, about 1.5 days, about 2 days, about3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8days, about 9 days, about 10 days, about 2 weeks, about 3 weeks, orabout 4 weeks after administration of one or more doses of the compoundof Formula I. In some embodiments, a phosphate level that is not anelevated phosphate level (e.g., in a blood sample) is a phosphate levelof at between about 2.5 and about 4.5 mg/dL (e.g., between about 2.5 andabout 3.0 mg/dL, about 2.5 and about 3.5 mg/dL, about 2.5 and about 4.0mg/dL, about 3.0 to about 4.5 mg/dL, about 3.5 to about 4.5 mg/dL, orabout 4.0 to about 4.5 mg/dL). In some embodiments, a phosphate levelthat is not an elevated phosphate level (e.g., in a blood sample) is aphosphate level of at less than about 5 mg/dL (e.g., less than about 4.5mg/dL, 4.0 mg/dL, 3.5 mg/dL, or 3.0 mg/dL, or 2.5 mg d/L). In someembodiments, an additional therapy or therapeutic agent is not an FGFR1inhibitor.

For example, provided herein are methods for treating a FGFR-associatedcancer in a subject previously administered one or more doses of a firstFGFR1 inhibitor and previously demonstrating an elevated phosphatelevel, the method comprising administering a compound of Formula I, or apharmaceutically acceptable salt or solvate thereof as a monotherapy orin conjunction with an additional therapy or therapeutic agent to thesubject. In some embodiments, following administration of a compound ofFormula I, the methods further comprise determine that a sample from thesubject does not demonstrate an elevated phosphate level. In someembodiments, the first FGFR1 inhibitor is selected from the groupconsisting of brivanib, dovitinib, erdafitinib, nintedanib, orantinib,pemigatinib, ponatinib, rogaratinib, sulfatinib, ARQ-087, ASP5878,AZD4547, BGJ398, Debio 1347, E7090, HMPL-453, INCB054828, MAX-40279,PRN1371, and TAS-120. In some embodiments, demonstration of an elevatedphosphate level occurs about 1 day to about 12 days (e.g., about 1 dayto about 2 days, about 1 day to about 3 days about 1 day to about 4days, about 1 day to about 5 days, about 1 day to about 6 days, about 1day to about 7 days, about 1 day to about 8 days, about 1 day to about 9days, about 1 day to about 10 days, about 1 day to about 11 days, about2 days to about 12 days, about 3 days to about 12 days, about 4 days toabout 12 days, about 5 days to about 12 days, about 6 days to about 12days, about 7 days to about 12 days, about 8 days to about 12 days,about 9 days to about 12 days, about 10 days to about 12 days, about 11days to about 12 days, about 1 day, about 2 days, about 3 days, about 4days, about 5 days, about 6 days, about 7 days, about 8 days, about 9days, about 10 days, about 11 days, or about 12 days) followingadministration of one or more doses of a first FGFR inhibitor. In someembodiments, an elevated phosphate level is a phosphate level (e.g., ina blood sample) of at least about 5 mg/dL (e.g., at least about 5.5mg/dL, 6.0 mg/dL, 6.5 mg/dL, 7.0 mg/dL, 7.5 mg/dL, 8.0 mg/dL, 8.5 mg/dL,9.0 mg/dL, 9.5 mg/dL, or 10.0 mg/dL). In some embodiments, demonstrationof an elevated phosphate level comprises demonstrating an elevatedphosphate level and at least one of: (i) a calcium-phosphate product ofat least about 50 mg²/dL² and (ii) a serum creatinine level of grade 1or greater. In some embodiments, an elevated phosphate level isdemonstrated in comparison to an earlier sample from the same subject(e.g., before administration of one or more doses of a first FGFR1inhibitor). In some embodiments, demonstration of a phosphate level thatis not an elevated phosphate level occurs about 6 hours, about 12 hours,about 18 hours, about 1 day, about 1.5 days, about 2 days, about 3 days,about 4 days, about 5 days, about 6 days, about 7 days, about 8 days,about 9 days, about 10 days, about 2 weeks, about 3 weeks, or about 4weeks after administration of one or more doses of the compound ofFormula I. In some embodiments, a phosphate level that is not anelevated phosphate level (e.g., in a blood sample) is a phosphate levelof at between about 2.5 and about 4.5 mg/dL (e.g., between about 2.5 andabout 3.0 mg/dL, about 2.5 and about 3.5 mg/dL, about 2.5 and about 4.0mg/dL, about 3.0 to about 4.5 mg/dL, about 3.5 to about 4.5 mg/dL, orabout 4.0 to about 4.5 mg/dL). In some embodiments, a phosphate levelthat is not an elevated phosphate level (e.g., in a blood sample) is aphosphate level of at less than about 5 mg/dL (e.g., less than about 4.5mg/dL, 4.0 mg/dL, 3.5 mg/dL, or 3.0 mg/dL, or 2.5 mg d/L). In someembodiments, an additional therapy or therapeutic agent is not an FGFR1inhibitor.

For example, provided herein are methods for treating a FGFR-associatedcancer in a subject previously administered one or more doses of a firstFGFR1 inhibitor and previously demonstrating an elevated phosphatelevel, the method comprising administering a compound of Formula Iselected from Examples 1-30, or a pharmaceutically acceptable salt orsolvate thereof as a monotherapy or in conjunction with an additionaltherapy or therapeutic agent to the subject. In some embodiments,following administration of a compound of compound of Formula I selectedfrom Examples 1-30, the methods further determining that a sample fromthe subject does not demonstrate an elevated phosphate level. In someembodiments, the first FGFR1 inhibitor is selected from the groupconsisting of brivanib, dovitinib, erdafitinib, nintedanib, orantinib,pemigatinib, ponatinib, rogaratinib, sulfatinib, ARQ-087, ASP5878,AZD4547, BGJ398, Debio 1347, E7090, HMPL-453, INCB054828, MAX-40279,PRN1371, and TAS-120. In some embodiments, demonstration of an elevatedphosphate level occurs about 1 day to about 12 days (e.g., about 1 dayto about 2 days, about 1 day to about 3 days about 1 day to about 4days, about 1 day to about 5 days, about 1 day to about 6 days, about 1day to about 7 days, about 1 day to about 8 days, about 1 day to about 9days, about 1 day to about 10 days, about 1 day to about 11 days, about2 days to about 12 days, about 3 days to about 12 days, about 4 days toabout 12 days, about 5 days to about 12 days, about 6 days to about 12days, about 7 days to about 12 days, about 8 days to about 12 days,about 9 days to about 12 days, about 10 days to about 12 days, about 11days to about 12 days, about 1 day, about 2 days, about 3 days, about 4days, about 5 days, about 6 days, about 7 days, about 8 days, about 9days, about 10 days, about 11 days, or about 12 days) followingadministration of one or more doses of a first FGFR inhibitor. In someembodiments, an elevated phosphate level is a phosphate level (e.g., ina blood sample) of at least about 5 mg/dL (e.g., at least about 5.5mg/dL, 6.0 mg/dL, 6.5 mg/dL, 7.0 mg/dL, 7.5 mg/dL, 8.0 mg/dL, 8.5 mg/dL,9.0 mg/dL, 9.5 mg/dL, or 10.0 mg/dL). In some embodiments, demonstrationof an elevated phosphate level comprises demonstrating an elevatedphosphate level and at least one of: (i) a calcium-phosphate product ofat least about 50 mg²/dL² and (ii) a serum creatinine level of grade 1or greater. In some embodiments, an elevated phosphate level isdemonstrated in comparison to an earlier sample from the same subject(e.g., before administration of one or more doses of a first FGFR1inhibitor). In some embodiments, the first FGFR1 inhibitor has a FGFR1activity of less than about 500 nM in an in vitro FGFR1 kinase assay. Insome embodiments, demonstration of a phosphate level that is not anelevated phosphate level occurs about 6 hours, about 12 hours, about 18hours, about 1 day, about 1.5 days, about 2 days, about 3 days, about 4days, about 5 days, about 6 days, about 7 days, about 8 days, about 9days, about 10 days, about 2 weeks, about 3 weeks, or about 4 weeksafter administration of one or more doses of the compound of Formula Iselected from Examples 1-30. In some embodiments, a phosphate level thatis not an elevated phosphate level (e.g., in a blood sample) is aphosphate level of at between about 2.5 and about 4.5 mg/dL (e.g.,between about 2.5 and about 3.0 mg/dL, about 2.5 and about 3.5 mg/dL,about 2.5 and about 4.0 mg/dL, about 3.0 to about 4.5 mg/dL, about 3.5to about 4.5 mg/dL, or about 4.0 to about 4.5 mg/dL). In someembodiments, a phosphate level that is not an elevated phosphate level(e.g., in a blood sample) is a phosphate level of at less than about 5mg/dL (e.g., less than about 4.5 mg/dL, 4.0 mg/dL, 3.5 mg/dL, or 3.0mg/dL, or 2.5 mg d/L). In some embodiments, an additional therapy ortherapeutic agent is not an FGFR1 inhibitor.

For example, provided herein are methods of treating a subject having acancer that include: identifying a subject demonstrating an elevatedphosphate level and a FGFR-associated cancer (e.g., any of theFGFR-associated cancers described herein or known in the art); andadministering to the identified subject a compound of Formula I or apharmaceutically acceptable salt or solvate thereof, where, followingadministration of one or more doses of the compound of Formula I, thesubject does not demonstrate an elevated phosphate level. In someembodiments, the compound of Formula I is administered as a monotherapyor in conjunction with an additional therapy or therapeutic agent. Insome embodiments, the additional therapy or therapeutic agent is not aFGFR1 inhibitor. In some embodiments, the identifying step comprisesidentifying a subject exhibiting an elevated phosphate level and atleast one of: (i) a calcium-phosphate product of at least about 50mg²/dL² and (ii) a serum creatinine level of grade 1 or greater. Alsoprovided are methods of treating a subject identified as having anelevated phosphate level and a FGFR-associated cancer (e.g., any of theFGFR-associated cancers described herein or known in the art) thatinclude administering to the subject a compound of Formula I or apharmaceutically acceptable salt or solvate thereof, where, followingadministration of one or more doses of the compound of Formula I, thesubject does not demonstrate an elevated phosphate level. In someembodiments, the compound of Formula I is administered as a monotherapyor in conjunction with an additional therapy or therapeutic agent. Insome embodiments, the additional therapy or therapeutic agent is not aFGFR1 inhibitor. In some embodiments, the identified subject alsoexhibits at least one of: (i) a calcium-phosphate product of at leastabout 50 mg²/dL² and (i) a serum creatinine level of grade 1 or greater.In some embodiments, demonstration of an elevated phosphate level occursabout 1 day to about 12 days (e.g., about 1 day to about 2 days, about 1day to about 3 days about 1 day to about 4 days, about 1 day to about 5days, about 1 day to about 6 days, about 1 day to about 7 days, about 1day to about 8 days, about 1 day to about 9 days, about 1 day to about10 days, about 1 day to about 11 days, about 2 days to about 12 days,about 3 days to about 12 days, about 4 days to about 12 days, about 5days to about 12 days, about 6 days to about 12 days, about 7 days toabout 12 days, about 8 days to about 12 days, about 9 days to about 12days, about 10 days to about 12 days, about 11 days to about 12 days,about 1 day, about 2 days, about 3 days, about 4 days, about 5 days,about 6 days, about 7 days, about 8 days, about 9 days, about 10 days,about 11 days, or about 12 days) following administration of one or moredoses of a first FGFR1 inhibitor. In some embodiments, demonstration ofa phosphate level that is not an elevated phosphate level occurs about 6hours, about 12 hours, about 18 hours, about 1 day, about 1.5 days,about 2 days, about 3 days, about 4 days, about 5 days, about 6 days,about 7 days, about 8 days, about 9 days, about 10 days, about 2 weeks,about 3 weeks, or about 4 weeks after administration of one or moredoses of the compound of Formula I. In some embodiments, an elevatedphosphate level is a phosphate level (e.g., in a blood sample) of atleast about 5 mg/dL (e.g., at least about 5.5 mg/dL, 6.0 mg/dL, 6.5mg/dL, 7.0 mg/dL, 7.5 mg/dL, 8.0 mg/dL, 8.5 mg/dL, 9.0 mg/dL, 9.5 mg/dL,or 10.0 mg/dL). In some embodiments, demonstration of an elevatedphosphate level comprises demonstrating an elevated phosphate level andat least one of: (i) a calcium-phosphate product of at least about 50mg²/dL² and (ii) a serum creatinine level of grade 1 or greater. In someembodiments, an elevated phosphate level is demonstrated in comparisonto an earlier sample from the same subject (e.g., before administrationof one or more doses of a first FGFR1 inhibitor). In some embodiments, aphosphate level that is not an elevated phosphate level (e.g., in ablood sample) is a phosphate level of at between about 2.5 and about 4.5mg/dL (e.g., between about 2.5 and about 3.0 mg/dL, about 2.5 and about3.5 mg/dL, about 2.5 and about 4.0 mg/dL, about 3.0 to about 4.5 mg/dL,about 3.5 to about 4.5 mg/dL, or about 4.0 to about 4.5 mg/dL). In someembodiments, a phosphate level that is not an elevated phosphate level(e.g., in a blood sample) is a phosphate level of at less than about 5mg/dL (e.g., less than about 4.5 mg/dL, 4.0 mg/dL, 3.5 mg/dL, or 3.0mg/dL, or 2.5 mg d/L). In some embodiments, the first FGFR1 inhibitorhas a FGFR1 activity of less than about 500 nM in an in vitro FGFR1kinase assay.

For example, provided herein are methods for treating a FGFR-associatedcancer in a subject in need of such treatment, the method comprising (a)detecting a dysregulation of a FGFR gene, a FGFR kinase, or theexpression or activity or level of any of the same in a sample from thesubject; and (b) administering to the subject a therapeuticallyeffective amount of a first FGFR1 inhibitor. In some embodiments, themethods further comprise (after (b)) (c) determining whether a samplefrom a subject demonstrates an elevated phosphate level; and after aperiod of time, (d) administering a compound of Formula I, or apharmaceutically acceptable salt or solvate thereof as a monotherapy orin conjunction with an additional therapy or therapeutic agent to thesubject if the sample from the subject demonstrates an elevatedphosphate level; or (e) administering additional doses of the firstFGFR1 inhibitor of step (b) to the subject if the sample from thesubject does not demonstrate an elevated phosphate level. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a sample from a subject demonstrates an elevated phosphate leveland least one of: (i) a calcium-phosphate product of at least about 50mg²/dL² and (ii) a serum creatinine level of grade 1 or greater; andafter a period of time, (d) administering a compound of Formula I, or apharmaceutically acceptable salt or solvate thereof as a monotherapy orin conjunction with an additional therapy or therapeutic agent to thesubject if the sample from the subject demonstrates an elevatedphosphate level and least one of: (i) a calcium-phosphate product of atleast about 50 mg²/dL² and (ii) a serum creatinine level of grade 1 orgreater; or (e) administering additional doses of the first FGFR1inhibitor of step (b) to the subject if the sample from the subject doesnot demonstrate an elevated phosphate level and at least one of: (i) acalcium-phosphate product of at least about 50 mg²/dL² and (2) a serumcreatinine level of grade 1 or greater. In some embodiments, the FGFR1inhibitor of step (b) is selected from the group consisting of ARQ-087,ASP5878, AZD4547, BGJ398, brivanib, Debio 1347, dovitinib, E7090,erdafitinib, HMPL-453, INCB054828, lenvatinib, lucitanib, MAX-40279,nintedanib, orantinib, pemigatinib, ponatinib, PRN1371, rogaratinib,sutfatinib, and TAS-120. In some embodiments, the sample of step (c) isa blood sample. In some embodiments of any of these methods, step (b)further includes administering to the subject a phosphate binder. Insome embodiments, step (c) occurs about 1 to about 12 days (e.g., about1 day to about 2 days, about 1 day to about 3 days, about 1 day to about4 days, about 1 day to about 5 days, about 1 day to about 6 days, about1 day to about 7 days, about 1 day to about 8 days, about 1 day to about9 days, about 1 day to about 10 days, about 1 day to about 11 days,about 2 days to about 12 days, about 3 days to about 12 days, about 4days to about 12 days, about 5 days to about 12 days, about 6 days toabout 12 days, about 7 days to about 12 days, about 8 days to about 12days, about 9 days to about 12 days, about 10 days to about 12 days,about 11 days to about 12 days, about 1 day, about 2 days, about 3 days,about 4 days, about 5 days, about 6 days, about 7 days, about 8 days,about 9 days, about 10 days, about 11 days, or about 12 days) after step(b). In some embodiments, the period of time between step (c) and step(d) is about 1 day, about 1.5 days, about 2 days, about 3 days, about 4days, about 5 days, about 6 days, about 7 days, about 8 days, about 9days, about 10 days, about 2 weeks, about 3 weeks, about 1 month, about2 months, about 3 months, about 4 months, about 5 months, about 6months, about 7 months, about 8 months, about 9 months, about 10 months,about 11 months, about 1 year, about 1.5 years, about 2 years, about 3years, about 4 years, about 5 years, about 6 years, about 7 years, about8 years, about 9 years, about 10 years, about 12 years, about 14 years,about 16 years, about 18 years, about 20 years, about 22 years, about 24years, about 26 years, about 28 years, about 30 years, about 35 years,about 40 years, or about 50 years. In some embodiments, an elevatedphosphate level is a phosphate level (e.g., in a blood sample) of atleast about 5 mg/dL (e.g., at least about 5.5 mg/dL, 6.0 mg/dL, 6.5mg/dL, 7.0 mg/dL, 7.5 mg/dL, 8.0 mg/dL, 8.5 mg/dL, 9.0 mg/dL, 9.5 mg/dL,or 10.0 mg/dL). In some embodiments, demonstration of an elevatedphosphate level comprises demonstrating an elevated phosphate level andat least one of: (i) a calcium-phosphate product of at least about 50mg²/dL² and (ii) a serum creatinine level of grade 1 or greater. In someembodiments, an elevated phosphate level is demonstrated in comparisonto an earlier sample from the same subject (e.g., before administrationof one or more doses of a first FGFR1 inhibitor). In some embodiments,the first FGFR1 inhibitor has a FGFR1 activity of less than about 500 nMin an in vitro FGFR1 kinase assay.

For example, provided herein are methods for treating a FGFR-associatedcancer in a subject in need of such treatment, the method comprising (a)detecting a dysregulation of a FGFR gene, a FGFR kinase, or theexpression or activity or level of any of the same in a sample from thesubject; and (b) administering to the subject a therapeuticallyeffective amount of a first FGFR1 inhibitor. In some embodiments, themethods further comprise (after (b)) (c) determining whether a samplefrom a subject demonstrates an elevated phosphate level; and after aperiod of time, (d) administering a compound of Formula I selected fromExamples 1-30, or a pharmaceutically acceptable salt or solvate thereofas a monotherapy or in conjunction with an additional therapy ortherapeutic agent to the subject if the sample from the subjectdemonstrates an elevated phosphate level; or (e) administeringadditional doses of the first FGFR1 inhibitor of step (b) to the subjectif the sample from the subject does not demonstrate an elevatedphosphate level. In some embodiments, the methods further comprise(after (b)) (c) determining whether a sample from a subject demonstratesan elevated phosphate level and least one of: (i) a calcium-phosphateproduct of at least about 50 mg²/dL² and (ii) a serum creatinine levelof grade 1 or greater; and after a period of time, (d) administering acompound of Formula I selected from Examples 1-30, or a pharmaceuticallyacceptable salt or solvate thereof as a monotherapy or in conjunctionwith an additional therapy or therapeutic agent to the subject if thesample from the subject demonstrates an elevated phosphate level andleast one of: (i) a calcium-phosphate product of at least about 50mg²/dL² and (ii) a serum creatinine level of grade 1 or greater; or (e)administering additional doses of the first FGFR1 inhibitor of step (b)to the subject if the sample from the subject does not demonstrate anelevated phosphate level and at least one of: (i) a calcium-phosphateproduct of at least about 50 mg²/dL² and (2) a serum creatinine level ofgrade 1 or greater. In some embodiments, the FGFR1 inhibitor of step (b)is selected from the group consisting of ARQ-087, ASP5878, AZD4547,BGJ398, brivanib, Debio 1347, dovitinib, E7090, erdafitinib, HMPL-453,INCB054828, lenvatinib, lucitanib, MAX-40279, nintedanib, orantinib,pemigatinib, ponatinib, PRN1371, rogaratinib, sulfatinib, and TAS-120.In some embodiments, the sample of step (c) is a blood sample. In someembodiments of any of these methods, step (b) further includesadministering to the subject a phosphate binder. In some embodiments,step (c) occurs about 1 to about 12 days (e.g., about 1 day to about 2days, about 1 day to about 3 days, about 1 day to about 4 days, about 1day to about 5 days, about 1 day to about 6 days, about 1 day to about 7days, about 1 day to about 8 days, about 1 day to about 9 days, about 1day to about 10 days, about 1 day to about 11 days, about 2 days toabout 12 days, about 3 days to about 12 days, about 4 days to about 12days, about 5 days to about 12 days, about 6 days to about 12 days,about 7 days to about 12 days, about 8 days to about 12 days, about 9days to about 12 days, about 10 days to about 12 days, about 11 days toabout 12 days, about 1 day, about 2 days, about 3 days, about 4 days,about 5 days, about 6 days, about 7 days, about 8 days, about 9 days,about 10 days, about 11 days, or about 12 days) after step (b). In someembodiments, the period of time between step (c) and step (d) is about 1day, about 1.5 days, about 2 days, about 3 days, about 4 days, about 5days, about 6 days, about 7 days, about 8 days, about 9 days, about 10days, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about3 months, about 4 months, about 5 months, about 6 months, about 7months, about 8 months, about 9 months, about 10 months, about 11months, about 1 year, about 1.5 years, about 2 years, about 3 years,about 4 years, about 5 years, about 6 years, about 7 years, about 8years, about 9 years, about 10 years, about 12 years, about 14 years,about 16 years, about 18 years, about 20 years, about 22 years, about 24years, about 26 years, about 28 years, about 30 years, about 35 years,about 40 years, or about 50 years. In some embodiments, an elevatedphosphate level is a phosphate level (e.g., in a blood sample) of atleast about 5 mg/dL (e.g., at least about 5.5 mg/dL, 6.0 mg/dL, 6.5mg/dL, 7.0 mg/dL, 7.5 mg/dL, 8.0 mg/dL, 8.5 mg/dL, 9.0 mg/dL, 9.5 mg/dL,or 10.0 mg/dL). In some embodiments, demonstration of an elevatedphosphate level comprises demonstrating an elevated phosphate level andat least one of: (i) a calcium-phosphate product of at least about 50mg²/dL² and (ii) a serum creatinine level of grade 1 or greater. In someembodiments, an elevated phosphate level is demonstrated in comparisonto an earlier sample from the same subject (e.g., before administrationof one or more doses of a first FGFR1 inhibitor). In some embodiments,the first FGFR1 inhibitor has a FGFR1 activity of less than about 500 nMin an in vitro FGFR1 kinase assay.

In some embodiments, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting one or more fusion proteins of Table BAand/or one or more FGFR kinase protein pointmutations/insertions/deletions of Table BC in a sample from the subject;and (b) administering to the subject a therapeutically effective amountof a first FGFR1 inhibitor. In some embodiments, the methods furthercomprise (after (b)) (c) determining whether a sample from a subjectdemonstrates an elevated phosphate level; and after a period of time,(d) administering a compound of Formula I, or a pharmaceuticallyacceptable salt or solvate thereof as a monotherapy or in conjunctionwith an additional therapy or therapeutic agent to the subject if thesample from the subject demonstrates an elevated phosphate level; or (e)administering additional doses of the first FGFR1 inhibitor of step (b)to the subject if the sample from the subject does not demonstrate anelevated phosphate level. In some embodiments, the methods furthercomprise (after (b)) (c) determining whether a sample from a subjectdemonstrates an elevated phosphate level and least one of: (i) acalcium-phosphate product of at least about 50 mg²/dL² and (ii) a serumcreatinine level of grade 1 or greater; and after a period of time, (d)administering a compound of Formula I, or a pharmaceutically acceptablesalt or solvate thereof as a monotherapy or in conjunction with anadditional therapy or therapeutic agent to the subject if the samplefrom the subject demonstrates an elevated phosphate level and least oneof: (i) a calcium-phosphate product of at least about 50 mg²/dL² and(ii) a serum creatinine level of grade 1 or greater; or (e)administering additional doses of the first FGFR1 inhibitor of step (b)to the subject if the sample from the subject does not demonstrate anelevated phosphate level and least one of: (i) a calcium-phosphateproduct of at least about 50 mg²/dL² and (ii) a serum creatinine levelof grade 1 or greater. In some embodiments, the FGFR1 inhibitor of step(b) is selected from the group consisting of ARQ-087, ASP5878, AZD4547,BGJ398, brivanib, Debio 1347, dovitinib, E7090, erdafitinib, HMPL-453,INCB054828, lenvatinib, lucitanib, MAX-40279, nintedanib, orantinib,pemigatinib, ponatinib, PRN1371, rogaratinib, sulfatinib, and TAS-120.In some embodiments, the sample of step (c) is a blood sample. In someembodiments of any of these methods, step (b) further includesadministering to the subject a phosphate binder. In some embodiments,step (c) occurs about 1 to about 12 days (e.g., about 1 day to about 2days, about 1 day to about 3 days, about 1 day to about 4 days, about 1day to about 5 days, about 1 day to about 6 days, about 1 day to about 7days, about 1 day to about 8 days, about 1 day to about 9 days, about 1day to about 10 days, about 1 day to about 11 days, about 2 days toabout 12 days, about 3 days to about 12 days, about 4 days to about 12days, about 5 days to about 12 days, about 6 days to about 12 days,about 7 days to about 12 days, about 8 days to about 12 days, about 9days to about 12 days, about 10 days to about 12 days, about 11 days toabout 12 days, about 1 day, about 2 days, about 3 days, about 4 days,about 5 days, about 6 days, about 7 days, about 8 days, about 9 days,about 10 days, about 11 days, or about 12 days) after step (b). In someembodiments, the period of time between step (c) and step (d) is about 1day, about 1.5 days, about 2 days, about 3 days, about 4 days, about 5days, about 6 days, about 7 days, about 8 days, about 9 days, about 10days, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about3 months, about 4 months, about 5 months, about 6 months, about 7months, about 8 months, about 9 months, about 10 months, about 11months, about 1 year, about 1.5 years, about 2 years, about 3 years,about 4 years, about 5 years, about 6 years, about 7 years, about 8years, about 9 years, about 10 years, about 12 years, about 14 years,about 16 years, about 18 years, about 20 years, about 22 years, about 24years, about 26 years, about 28 years, about 30 years, about 35 years,about 40 years, or about 50 years. In some embodiments, an elevatedphosphate level is a phosphate level (e.g., in a blood sample) of atleast about 5 mg/dL (e.g., at least about 5.5 mg/dL, 6.0 mg/dL, 6.5mg/dL, 7.0 mg/dL, 7.5 mg/dL, 8.0 mg/dL, 8.5 mg/dL, 9.0 mg/dL, 9.5 mg/dL,or 10.0 mg/dL). In some embodiments, demonstration of an elevatedphosphate level comprises demonstrating an elevated phosphate level andat least one of: (i) a calcium-phosphate product of at least about 50mg²/dL² and (ii) a serum creatinine level of grade 1 or greater. In someembodiments, an elevated phosphate level is demonstrated in comparisonto an earlier sample from the same subject (e.g., before administrationof one or more doses of a first FGFR1 inhibitor). In some embodiments,the first FGFR1 inhibitor has a FGFR1 activity of less than about 500 nMin an in vitro FGFR1 kinase assay.

In some embodiments, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting one or more fusion proteins of Table BAand/or one or more FGFR kinase protein pointmutations/insertions/deletions of Table BC in a sample from the subject;and (b) administering to the subject a therapeutically effective amountof a first FGFR1 inhibitor. In some embodiments, the methods furthercomprise (after (b)) (c) determining whether a sample from a subjectdemonstrates an elevated phosphate level; and after a period of time,(d) administering a compound of Formula I selected from Examples 1-30,or a pharmaceutically acceptable salt or solvate thereof as amonotherapy or in conjunction with an additional therapy or therapeuticagent to the subject if the sample from the subject demonstrates anelevated phosphate level; or (e) administering additional doses of thefirst FGFR1 inhibitor of step (b) to the subject if the sample from thesubject does not demonstrate an elevated phosphate level. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a sample from a subject demonstrates an elevated phosphate leveland least one of: (i) a calcium-phosphate product of at least about 50mg²/dL² and (ii) a serum creatinine level of grade 1 or greater; andafter a period of time, (d) administering a compound of Formula Iselected from Examples 1-30, or a pharmaceutically acceptable salt orsolvate thereof as a monotherapy or in conjunction with an additionaltherapy or therapeutic agent to the subject if the sample from thesubject demonstrates an elevated phosphate level and least one of: (i) acalcium-phosphate product of at least about 50 mg²/dL² and (ii) a serumcreatinine level of grade 1 or greater; or (e) administering additionaldoses of the first FGFR1 inhibitor of step (b) to the subject if thesample from the subject does not demonstrate an elevated phosphate leveland least one of: (i) a calcium-phosphate product of at least about 50mg²/dL² and (ii) a serum creatinine level of grade 1 or greater. In someembodiments, the FGFR1 inhibitor of step (b) is selected from the groupconsisting of ARQ-087, ASP5878, AZD4547, BGJ398, brivanib, Debio 1347,dovitinib, E7090, erdafitinib, HMPL-453, INCB054828, lenvatinib,lucitanib, MAX-40279, nintedanib, orantinib, pemigatinib, ponatinib,PRN1371, rogaratinib, sulfatinib, and TAS-120. In some embodiments, thesample of step (c) is a blood sample. In some embodiments of any ofthese methods, step (b) further includes administering to the subject aphosphate binder. In some embodiments, step (c) occurs about 1 to about12 days (e.g., about 1 day to about 2 days, about 1 day to about 3 days,about 1 day to about 4 days, about 1 day to about 5 days, about 1 day toabout 6 days, about 1 day to about 7 days, about 1 day to about 8 days,about 1 day to about 9 days, about 1 day to about 10 days, about 1 dayto about 11 days, about 2 days to about 12 days, about 3 days to about12 days, about 4 days to about 12 days, about 5 days to about 12 days,about 6 days to about 12 days, about 7 days to about 12 days, about 8days to about 12 days, about 9 days to about 12 days, about 10 days toabout 12 days, about 11 days to about 12 days, about 1 day, about 2days, about 3 days, about 4 days, about 5 days, about 6 days, about 7days, about 8 days, about 9 days, about 10 days, about 11 days, or about12 days) after step (b). In some embodiments, the period of time betweenstep (c) and step (d) is about 1 day, about 1.5 days, about 2 days,about 3 days, about 4 days, about 5 days, about 6 days, about 7 days,about 8 days, about 9 days, about 10 days, about 2 weeks, about 3 weeks,about 1 month, about 2 months, about 3 months, about 4 months, about 5months, about 6 months, about 7 months, about 8 months, about 9 months,about 10 months, about 11 months, about 1 year, about 1.5 years, about 2years, about 3 years, about 4 years, about 5 years, about 6 years, about7 years, about 8 years, about 9 years, about 10 years, about 12 years,about 14 years, about 16 years, about 18 years, about 20 years, about 22years, about 24 years, about 26 years, about 28 years, about 30 years,about 35 years, about 40 years, or about 50 years. In some embodiments,an elevated phosphate level is a phosphate level (e.g., in a bloodsample) of at least about 5 mg/dL (e.g., at least about 5.5 mg/dL, 6.0mg/dL, 6.5 mg/dL, 7.0 mg/dL, 7.5 mg/dL, 8.0 mg/dL, 8.5 mg/dL, 9.0 mg/dL,9.5 mg/dL, or 10.0 mg/dL). In some embodiments, demonstration of anelevated phosphate level comprises demonstrating an elevated phosphatelevel and at least one of: (i) a calcium-phosphate product of at leastabout 50 mg²/dL² and (ii) a serum creatinine level of grade 1 orgreater. In some embodiments, an elevated phosphate level isdemonstrated in comparison to an earlier sample from the same subject(e.g., before administration of one or more doses of a first FGFR1inhibitor). In some embodiments, the first FGFR1 inhibitor has a FGFR1activity of less than about 500 nM in an in vitro FGFR1 kinase assay.

In some embodiments, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting the fusion protein FGFR3-TACC3 in asample from the subject; and (b) administering to the subject atherapeutically effective amount of a first FGFR1 inhibitor. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a sample from a subject demonstrates an elevated phosphatelevel; and after a period of time, (d) administering a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereofselected from the group consisting of a compound of Formula I, or apharmaceutically acceptable salt or solvate thereof as a monotherapy orin conjunction with an additional therapy or therapeutic agent to thesubject if the sample from the subject demonstrates an elevatedphosphate level; or (e) administering additional doses of the firstFGFR1 inhibitor of step (b) to the subject if the sample from thesubject does not demonstrate an elevated phosphate level. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a sample from a subject demonstrates an elevated phosphate leveland least one of: (i) a calcium-phosphate product of at least about 50mg²/dL² and (ii) a serum creatinine level of grade 1 or greater; andafter a period of time, (d) administering a compound of Formula I or apharmaceutically acceptable salt or solvate thereof selected from thegroup consisting of a compound of Formula I, or a pharmaceuticallyacceptable salt or solvate thereof as a monotherapy or in conjunctionwith an additional therapy or therapeutic agent to the subject if thesample from the subject demonstrates an elevated phosphate level andleast one of: (i) a calcium-phosphate product of at least about 50mg²/dL² and (ii) a serum creatinine level of grade 1 or greater; or (e)administering additional doses of the first FGFR1 inhibitor of step (b)to the subject if the sample from the subject does not demonstrate anelevated phosphate level and least one of: (i) a calcium-phosphateproduct of at least about 50 mg²/dL² and (ii) a serum creatinine levelof grade 1 or greater. In some embodiments, the FGFR1 inhibitor of step(b) is selected from the group consisting of ARQ-087, ASP5878, AZD4547,BGJ398, brivanib, Debio 1347, dovitinib, E7090, erdafitinib, HMPL-453,INCB054828, lenvatinib, lucitanib, MAX-40279, nintedanib, orantinib,pemigatinib, ponatinib, PRN1371, rogaratinib, sulfatinib, and TAS-120.In some embodiments, the sample of step (c) is a blood sample. In someembodiments of any of these methods, step (b) further includesadministering to the subject a phosphate binder. In some embodiments,step (c) occurs about 1 to about 12 days (e.g., about 1 day to about 2days, about 1 day to about 3 days, about 1 day to about 4 days, about 1day to about 5 days, about 1 day to about 6 days, about 1 day to about 7days, about 1 day to about 8 days, about 1 day to about 9 days, about 1day to about 10 days, about 1 day to about 11 days, about 2 days toabout 12 days, about 3 days to about 12 days, about 4 days to about 12days, about 5 days to about 12 days, about 6 days to about 12 days,about 7 days to about 12 days, about 8 days to about 12 days, about 9days to about 12 days, about 10 days to about 12 days, about 11 days toabout 12 days, about 1 day, about 2 days, about 3 days, about 4 days,about 5 days, about 6 days, about 7 days, about 8 days, about 9 days,about 10 days, about 11 days, or about 12 days) after step (b). In someembodiments, the period of time between step (c) and step (d) is about 1day, about 1.5 days, about 2 days, about 3 days, about 4 days, about 5days, about 6 days, about 7 days, about 8 days, about 9 days, about 10days, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about3 months, about 4 months, about 5 months, about 6 months, about 7months, about 8 months, about 9 months, about 10 months, about 11months, about 1 year, about 1.5 years, about 2 years, about 3 years,about 4 years, about 5 years, about 6 years, about 7 years, about 8years, about 9 years, about 10 years, about 12 years, about 14 years,about 16 years, about 18 years, about 20 years, about 22 years, about 24years, about 26 years, about 28 years, about 30 years, about 35 years,about 40 years, or about 50 years. In some embodiments, an elevatedphosphate level is a phosphate level (e.g., in a blood sample) of atleast about 5 mg/dL (e.g., at least about 5.5 mg/dL, 6.0 mg/dL, 6.5mg/dL, 7.0 mg/dL, 7.5 mg/dL, 8.0 mg/dL, 8.5 mg/dL, 9.0 mg/dL, 9.5 mg/dL,or 10.0 mg/dL). In some embodiments, demonstration of an elevatedphosphate level comprises demonstrating an elevated phosphate level andat least one of: (i) a calcium-phosphate product of at least about 50mg²/dL² and (ii) a serum creatinine level of grade 1 or greater. In someembodiments, an elevated phosphate level is demonstrated in comparisonto an earlier sample from the same subject (e.g., before administrationof one or more doses of a first FGFR1 inhibitor). In some embodiments,the first FGFR1 inhibitor has a FGFR1 activity of less than about 500 nMin an in vitro FGFR1 kinase assay.

In some embodiments, provided herein are methods for treating aFGFR-associated cancer in a subject in need of such treatment, themethod comprising (a) detecting the fusion protein FGFR3-TACC3 in asample from the subject; and (b) administering to the subject atherapeutically effective amount of a first FGFR1 inhibitor. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a sample from a subject demonstrates an elevated phosphatelevel; and after a period of time, (d) administering a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereofselected from the group consisting of a compound of Formula I selectedfrom Examples 1-30, or a pharmaceutically acceptable salt or solvatethereof as a monotherapy or in conjunction with an additional therapy ortherapeutic agent to the subject if the sample from the subjectdemonstrates an elevated phosphate level; or (e) administeringadditional doses of the first FGFR1 inhibitor of step (b) to the subjectif the sample from the subject does not demonstrate an elevatedphosphate level. In some embodiments, the methods further comprise(after (b)) (c) determining whether a sample from a subject demonstratesan elevated phosphate level and least one of: (i) a calcium-phosphateproduct of at least about 50 mg²/dL² and (ii) a serum creatinine levelof grade 1 or greater; and after a period of time, (d) administering acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof selected from the group consisting of a compound of Formula Iselected from Examples 1-30, or a pharmaceutically acceptable salt orsolvate thereof as a monotherapy or in conjunction with an additionaltherapy or therapeutic agent to the subject if the sample from thesubject demonstrates an elevated phosphate level and least one of: (i) acalcium-phosphate product of at least about 50 mg²/dL² and (ii) a serumcreatinine level of grade 1 or greater; or (e) administering additionaldoses of the first FGFR1 inhibitor of step (b) to the subject if thesample from the subject does not demonstrate an elevated phosphate leveland least one of: (i) a calcium-phosphate product of at least about 50mg²/dL² and (ii) a serum creatinine level of grade 1 or greater. In someembodiments, the FGFR1 inhibitor of step (b) is selected from the groupconsisting of ARQ-087, ASP5878, AZD4547, BGJ398, brivanib, Debio 1347,dovitinib, E7090, erdafitinib, HMPL-453, INCB054828, lenvatinib,lucitanib, MAX-40279, nintedanib, orantinib, pemigatinib, ponatinib,PRN1371, rogaratinib, sulfatinib, and TAS-120. In some embodiments, thesample of step (c) is a blood sample. In some embodiments of any ofthese methods, step (b) further includes administering to the subject aphosphate binder. In some embodiments, step (c) occurs about 1 to about12 days (e.g., about 1 day to about 2 days, about 1 day to about 3 days,about 1 day to about 4 days, about 1 day to about 5 days, about 1 day toabout 6 days, about 1 day to about 7 days, about 1 day to about 8 days,about 1 day to about 9 days, about 1 day to about 10 days, about 1 dayto about 11 days, about 2 days to about 12 days, about 3 days to about12 days, about 4 days to about 12 days, about 5 days to about 12 days,about 6 days to about 12 days, about 7 days to about 12 days, about 8days to about 12 days, about 9 days to about 12 days, about 10 days toabout 12 days, about 11 days to about 12 days, about 1 day, about 2days, about 3 days, about 4 days, about 5 days, about 6 days, about 7days, about 8 days, about 9 days, about 10 days, about 11 days, or about12 days) after step (b). In some embodiments, the period of time betweenstep (c) and step (d) is about 1 day, about 1.5 days, about 2 days,about 3 days, about 4 days, about 5 days, about 6 days, about 7 days,about 8 days, about 9 days, about 10 days, about 2 weeks, about 3 weeks,about 1 month, about 2 months, about 3 months, about 4 months, about 5months, about 6 months, about 7 months, about 8 months, about 9 months,about 10 months, about 11 months, about 1 year, about 1.5 years, about 2years, about 3 years, about 4 years, about 5 years, about 6 years, about7 years, about 8 years, about 9 years, about 10 years, about 12 years,about 14 years, about 16 years, about 18 years, about 20 years, about 22years, about 24 years, about 26 years, about 28 years, about 30 years,about 35 years, about 40 years, or about 50 years. In some embodiments,an elevated phosphate level is a phosphate level (e.g., in a bloodsample) of at least about 5 mg/dL (e.g., at least about 5.5 mg/dL, 6.0mg/dL, 6.5 mg/dL, 7.0 mg/dL, 7.5 mg/dL, 8.0 mg/dL, 8.5 mg/dL, 9.0 mg/dL,9.5 mg/dL, or 10.0 mg/dL). In some embodiments, demonstration of anelevated phosphate level comprises demonstrating an elevated phosphatelevel and at least one of: (i) a calcium-phosphate product of at leastabout 50 mg²/dL² and (ii) a serum creatinine level of grade 1 orgreater. In some embodiments, an elevated phosphate level isdemonstrated in comparison to an earlier sample from the same subject(e.g., before administration of one or more doses of a first FGFR1inhibitor). In some embodiments, the first FGFR1 inhibitor has a FGFR1activity of less than about 500 nM in an in vitro FGFR1 kinase assay.

Also provided herein are methods of treating a FGFR-associated cancer ina subject, the method comprising administering to the subject a compoundof Formula I or a pharmaceutically acceptable salt or solvate thereof,where, following administration of the compound of Formula I or apharmaceutically acceptable salt or solvate thereof, a sample from thesubject has a phosphate level that is lower than the phosphate level ofa sample from a second subject having an FGFR-associated cancerfollowing administration of a compound that is not a compound of FormulaI or a pharmaceutically acceptable salt or solvate thereof. In someembodiments, the compound that is not a compound of compound that is nota compound of Formula I or a pharmaceutically acceptable salt or solvatethereof is a FGFR1 inhibitor. In some embodiments, the compound that isnot a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof is selected from the group consisting of ARQ-087,ASP5878, AZD4547, B-701, BAY1179470, BAY1187982, BGJ398, brivanib, Debio1347, dovitinib, E7090, erdafitinib, FPA144, HMPL-453, INCB054828,lenvatinib, lucitanib, LY3076226, MAX-40279, nintedanib, orantinib,pemigatinib, ponatinib, PRN1371, rogaratinib, sulfatinib, and TAS-120.In some embodiments, the compound that is not a compound of Formula I ora pharmaceutically acceptable salt or solvate thereof has an FGFR1activity of less than 50 nM in an in vitro FGFR1 kinase assay. In someembodiments, the sample from the subject and the sample from the secondsubject are blood samples. In some embodiments, the sample from thesubject is taken about 6 hours, about 12 hours, about 18 hours, about 1day, about 1.5 days, about 2 days, about 3 days, about 4 days, about 5days, about 6 days, about 7 days, about 8 days, about 9 days, about 10days, about 2 weeks, about 3 weeks, or about 4 weeks after administeringto the subject one or more doses of the compound of Formula I. In someembodiments, the sample from the second subject is taken about 6 hours,about 12 hours, about 18 hours, about 1 day, about 1.5 days, about 2days, about 3 days, about 4 days, about 5 days, about 6 days, about 7days, about 8 days, about 9 days, about 10 days, about 2 weeks, about 3weeks, or about 4 weeks after administering to the subject one or moredoses of the compound that is not a compound of Formula I. In someembodiments, the sample from the subject and the sample from the secondsubject are taken at approximately equal times after administering oneor more doses of a compound of Formula I or a compound that is not acompound of Formula I, respectively. In some embodiments, the samplefrom the subject demonstrates a phosphate level of between about 2.5 andabout 4.5 mg/dL (e.g., between about 2.5 and about 3.0 mg/dL, about 2.5and about 3.5 mg/dL, about 2.5 and about 4.0 mg/dL, about 3.0 to about4.5 mg/dL, about 3.5 to about 4.5 mg/dL, or about 4.0 to about 4.5mg/dL). In some embodiments, the sample from the subject demonstrates aphosphate level of at less than about 5 mg/dL (e.g., less than about 4.5mg/dL, 4.0 mg/dL, 3.5 mg/dL, or 3.0 mg/dL, or 2.5 mg d/L). In someembodiments, the method further comprises reducing the dose of a FGFR1inhibitor administered to the subject, ceasing to administer a FGFR1 tothe subject, or not administering a FGFR1 inhibitor to the subject.

Also provided are methods of treating a FGFR-associated cancer in asubject, the method comprising administering to the subject a compoundof Formula I or a pharmaceutically acceptable salt or solvate thereof,wherein following administration of the compound of Formula I, a samplefrom the subject does not demonstrate an elevated phosphate level. Insome embodiments, the sample from the subject is a blood sample. In someembodiments, the sample from the subject is taken about 6 hours, about12 hours, about 18 hours, about 1 day, about 1.5 days, about 2 days,about 3 days, about 4 days, about 5 days, about 6 days, about 7 days,about 8 days, about 9 days, about 10 days, about 2 weeks, about 3 weeks,or about 4 weeks after administering to the subject one or more doses ofthe compound of Formula I. In some embodiments, a phosphate level thatis not an elevated phosphate level (e.g., in a blood sample) is aphosphate level of between about 2.5 and about 4.5 mg/dL (e.g., betweenabout 2.5 and about 3.0 mg/dL, about 2.5 and about 3.5 mg/dL, about 2.5and about 4.0 mg/dL, about 3.0 to about 4.5 mg/dL, about 3.5 to about4.5 mg/dL, or about 4.0 to about 4.5 mg/dL). In some embodiments, aphosphate level that is not an elevated phosphate level (e.g., in ablood sample) is a phosphate level of at less than about 5 mg/dL (e.g.,less than about 4.5 mg/dL, 4.0 mg/dL, 3.5 mg/dL, or 3.0 mg/dL, or 2.5 mgd/L). In some embodiments, the method further comprises reducing thedose of a FGFR1 inhibitor administered to the subject, ceasing toadminister a FGFR1 to the subject, or not administering a FGFR1inhibitor to the subject. In some embodiments, the FGFR1 inhibitor isselected from the group consisting of brivanib, dovitinib, erdafitinib,nintedanib, orantinib, pemigatinib, ponatinib, rogaratinib, sulfatinib,ARQ-087, ASP5878, AZD4547, BGJ398, Debio 1347, E7090, HMPL-453,INCB054828, MAX-40279, PRN1371, and TAS-120. In some embodiments, theFGFR1 inhibitor has an FGFR1 activity of less than 50 nM in an in vitroFGFR1 kinase assay.

Also provided are methods of reducing the risk of an elevated serumphosphate level (e.g., hyperphosphatemia) in a subject with aFGFR-associated cancer, the method comprising administering to thesubject a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments, the method further comprisesreducing the dose of a FGFR1 inhibitor administered to the subject,ceasing to administer a FGFR1 to the subject, or not administering aFGFR1 inhibitor to the subject. In some embodiments, the FGFR1 inhibitoris selected from the group consisting of brivanib, dovitinib,erdafitinib, nintedanib, orantinib, pemigatinib, ponatinib, rogaratinib,sulfatinib, ARQ-087, ASP5878, AZD4547, BGJ398, Debio 1347, E7090,HMPL-453, INCB054828, MAX-40279, PRN1371, and TAS-120.

Also provided are methods of reversing elevated serum phosphate level(e.g., hyperphosphatemia) in a subject with a FGFR-associated cancerbeing treated with a FGFR1 inhibitor, the method comprising (a) reducingthe dose or ceasing administration of the FGFR1 inhibitor; and (b)administering to the subject a compound of Formula I or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the FGFR1 inhibitor is selected from the group consistingof brivanib, dovitinib, erdafitinib, nintedanib, orantinib, pemigatinib,ponatinib, rogaratinib, sulfatinib, ARQ-087, ASP5878, AZD4547, BGJ398,Debio 1347, E7090, HMPL-453, INCB054828, MAX-40279, PRN1371, andTAS-1200. In some embodiments, the FGFR1 inhibitor has an FGFR1 activityof less than 50 nM in an in vitro FGFR1 kinase assay. Also providedherein are methods of treating a FGFR-associated cancer in a subject,the method comprising administering to the subject a compound of FormulaI or a pharmaceutically acceptable salt or solvate thereof, where,following administration of the compound of Formula I or apharmaceutically acceptable salt or solvate thereof, a sample from thesubject has a phosphate level that is lower than the phosphate level ofa sample from a second subject having an FGFR-associated cancerfollowing administration of a compound that is not a compound of FormulaI or a pharmaceutically acceptable salt or solvate thereof. In someembodiments, the compound that is not a compound of compound that is nota compound of Formula I or a pharmaceutically acceptable salt or solvatethereof is a FGFR1 inhibitor. In some embodiments, the compound that isnot a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof is selected from the group consisting of ARQ-087,ASP5878, AZD4547, B-701, BAY1179470, BAY1187982, BGJ398, brivanib, Debio1347, dovitinib, E7090, erdafitinib, FPA144, HMPL-453, INCB054828,lenvatinib, lucitanib, LY3076226, MAX-40279, nintedanib, orantinib,pemigatinib, ponatinib, PRN1371, rogaratinib, sulfatinib, and TAS-120.In some embodiments, the compound that is not a compound of Formula I ora pharmaceutically acceptable salt or solvate thereof has an FGFR1activity of less than 50 nM in an in vitro FGFR1 kinase assay. In someembodiments, the sample from the subject and the sample from the secondsubject are blood samples. In some embodiments, the sample from thesubject is taken about 6 hours, about 12 hours, about 18 hours, about 1day, about 1.5 days, about 2 days, about 3 days, about 4 days, about 5days, about 6 days, about 7 days, about 8 days, about 9 days, about 10days, about 2 weeks, about 3 weeks, or about 4 weeks after administeringto the subject one or more doses of the compound of Formula I. In someembodiments, the sample from the second subject is taken about 6 hours,about 12 hours, about 18 hours, about 1 day, about 1.5 days, about 2days, about 3 days, about 4 days, about 5 days, about 6 days, about 7days, about 8 days, about 9 days, about 10 days, about 2 weeks, about 3weeks, or about 4 weeks after administering to the subject one or moredoses of the compound that is not a compound of Formula I. In someembodiments, the sample from the subject and the sample from the secondsubject are taken at approximately equal times after administering oneor more doses of a compound of Formula I or a compound that is not acompound of Formula I, respectively. In some embodiments, the samplefrom the subject demonstrates a phosphate level of between about 2.5 andabout 4.5 mg/dL (e.g., between about 2.5 and about 3.0 mg/dL, about 2.5and about 3.5 mg/dL, about 2.5 and about 4.0 mg/dL, about 3.0 to about4.5 mg/dL, about 3.5 to about 4.5 mg/dL, or about 4.0 to about 4.5mg/dL). In some embodiments, the sample from the subject demonstrates aphosphate level of at less than about 5 mg/dL (e.g., less than about 4.5mg/dL, 4.0 mg/dL, 3.5 mg/dL, or 3.0 mg/dL, or 2.5 mg d/L). In someembodiments, the method further comprises reducing the dose of a FGFR1inhibitor administered to the subject, ceasing to administer a FGFR1 tothe subject, or not administering a FGFR1 inhibitor to the subject.

Also provided herein are methods of treating a FGFR-associated cancer(e.g., any of the FGFR-associated cancers described herein or known inthe art) in a subject that includes administering a therapeuticallyeffective dose of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof, or a pharmaceutical compositionincluding a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof, to a subject identified or diagnosed as having aFGFR-associated cancer over a treatment period of at least 8 days, wherethe subject is determined to have about the same or a decreased level ofphosphate in one or more sample(s) including blood, serum, or plasmaobtained from the subject over the treatment period as compared to areference level of phosphate (e.g., any of the reference levels ofphosphate described herein). In some embodiments of any of thesemethods, the subject is identified or diagnosed as having aFGFR-associated cancer using any of the methods described herein orknown in the art. Some embodiments of any of these methods can furtherinclude identifying or diagnosing a subject as having a FGFR-associatedcancer using any of the methods described herein or known in the art. Insome embodiments, the treatment period of at least 8 days can be any ofthe exemplary treatment periods (or ranges of treatment periods)described herein. In some embodiments, the subject is administered adaily dose of a compound of Formula I or a pharmaceutically acceptablesalt or solvate thereof, or a pharmaceutical composition including acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof (e.g., any of the pharmaceutical compositions described herein)over the treatment period.

Also provided are methods of treating a FGFR-associated cancer (e.g.,any of the FGFR-associated cancers described herein or known in the art)that include administering a therapeutically effective dose of acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof to a subject identified or diagnosed as having a FGFR-associatedcancer, wherein the subject is not administered a phosphate binder(e.g., any of the phosphate binders described herein or known in theart). In some embodiments of any of these methods, the subject isidentified or diagnosed as having a FGFR-associated cancer using any ofthe methods described herein or known in the art. Some embodiments ofany of these methods can further include identifying or diagnosing asubject as having a FGFR-associated cancer using any of the methodsdescribed herein or known in the art. In some embodiments, the subjectis administered a daily dose of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof.

Also provided herein are methods of treating a FGFR-associated cancer(e.g., any FGFR-associated cancer described herein or known in the art)in a subject that include administering a therapeutically effective doseof a compound of Formula I or pharmaceutically acceptable salt orsolvate thereof to a subject identified or diagnosed as having aFGFR-associated cancer, wherein the subject is further administered aphosphate binder (e.g., any of the phosphate binders described herein,e.g., sevelamer hydrochloride). Some embodiments of any of these methodscan further include identifying or diagnosing a subject as having aFGFR-associated cancer using any of the methods described herein orknown in the art. In some embodiments, the subject is administered adaily dose of a compound of Formula I or a pharmaceutically acceptablesalt or solvate thereof.

Also provided herein are methods of treating a FGFR-associated disease(e.g., a FGFR-associated cancer, e.g., any of the FGFR-associatedcancers described herein or known in the art) in a subject that include:(a) administering to a subject identified or diagnosed as having aFGFR-associated disease (e.g., a FGFR-associated cancer) one or moredoses of a first FGFR inhibitor over a treatment period; (b) determininga level of phosphate in a sample including blood, serum, or plasmaobtained from the subject after the treatment period; (c) selecting asubject having an elevated level of phosphate in the biological sampleas compared to a reference level of phosphate; and (d) ceasingadministration of the first FGFR inhibitor (or instructing the selectedsubject to cease administration) and initiating administration of atherapeutically effective amount of a compound of Formula I orpharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalagent or composition comprising a compound of Formula I orpharmaceutically acceptable salt or solvate thereof (e.g., any of thepharmaceutical agents or compositions described herein), to the selectedsubject. Some embodiments of these methods can further includeidentifying or diagnosing a subject as having a FGFR-associated disease(e.g., a FGFR-associated cancer) using any of the methods describedherein.

Administration of a first FGFR inhibitor to a subject can cause adverseeffects. In some embodiments, the adverse effects can include one ormore of: anorexia, asthenia, constipation, decreased appetite, diarrhea,dry mouth, elevated phosphate level (e.g., hyperphosphatemia), fatigue,liver enzyme abnormalities, malaise, muscle aches, nail changes, nausea,soft tissue calcification, and stomatitis. Accordingly, provided hereinare methods useful when a first FGFR inhibitor causes adverse affects.

Provided are methods of treating a subject having a FGFR-associatedcancer (e.g., any of the FGFR-associated cancers described herein orknown in the art) that include: administering a therapeuticallyeffective dose of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof to a subject identified or diagnosedas having a FGFR-associated cancer, where the subject does notexperience or is less likely to experience one or more (e.g., two,three, four, five, six, seven, eight, nine, ten, eleven, twelve,thirteen, fourteen, or fifteen) of anorexia, asthenia, constipation,decreased appetite, diarrhea, dry mouth, elevated phosphate level (e.g.,hyperphosphatemia), fatigue, liver enzyme abnormalities, malaise, muscleaches, nail changes, nausea, soft tissue calcification, and stomatitisover the treatment period or after the treatment period (e.g., ascompared to a subject or a population of subjects having the sameFGFR-associated cancer and administered a therapeutically effective doseof a FGFR inhibitor that is not a compound of Formula I or apharmaceutically acceptable salt or solvate thereof). Some embodimentsof any of these methods can further include identifying or diagnosing asubject as having a FGFR-associated cancer using any of the methodsdescribed herein or known in the art. In some embodiments, the subjectis administered a daily dose of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof.

In some embodiments of the methods described herein, the subject isadministered a compound of Formula I and not administered a phosphatebinder (e.g., any of the phosphate binders described herein or known inthe art). In such methods, the subject can be, e.g., less likely toexperience one or more (e.g., two, three, four, five, six, seven, eight,nine, ten, eleven, twelve, thirteen, fourteen, or fifteen) of anorexia,asthenia, constipation, decreased appetite, diarrhea, dry mouth,elevated phosphate level (e.g., hyperphosphatemia), fatigue, liverenzyme abnormalities, malaise, muscle aches, nail changes, nausea, softtissue calcification, and stomatitis over the treatment period or afterthe treatment period (e.g., as compared to a subject or a population ofsubjects having the same FGFR-associated cancer and administered atherapeutically effective dose of a FGFR inhibitor that is not acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof, and is not administered a phosphate binder).

In some embodiments of the methods described herein, the subject isadministered a phosphate binder (e.g., any of the phosphate bindersdescribed herein, e.g., sevelamer hydrochloride). In such methods, thesubject can be, e.g., less likely to experience one or more (e.g., two,three, four, five, six, seven, eight, nine, ten, eleven, twelve,thirteen, fourteen, or fifteen) of anorexia, asthenia, constipation,decreased appetite, diarrhea, dry mouth, elevated phosphate level (e.g.,hyperphosphatemia), fatigue, liver enzyme abnormalities, malaise, muscleaches, nail changes, nausea, soft tissue calcification, and stomatitisover the treatment period or after the treatment period (e.g., ascompared to a subject or a population of subjects having the sameFGFR-associated cancer and administered a therapeutically effective doseof a FGFR inhibitor that is not a compound of Formula I or apharmaceutically acceptable salt or solvate thereof, and is administeredthe same phosphate binder).

In some embodiments, a subject is less likely to experience one or more(e.g., two, three, four, five, six, seven, eight, nine, ten, eleven,twelve, thirteen, fourteen, or fifteen) of anorexia, asthenia,constipation, decreased appetite, diarrhea, dry mouth, elevatedphosphate level (e.g., hyperphosphatemia), fatigue, liver enzymeabnormalities, malaise, muscle aches, nail changes, nausea, soft tissuecalcification, and stomatitis (e.g., as compared to a subject or apopulation of subjects having the same FGFR-associated cancer andadministered a therapeutically effective dose of a FGFR inhibitor thatis not a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof, or a pharmaceutical composition including a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof, andis administered the same phosphate binder).

The level of soft tissue calcification can be detected/determined in asubject by a medical professional using, e.g., ultrasound, radiography,computed tomography, and magnetic resonance imaging. The level ofstomatitis, dry mouth, nail changes, fatigue, asthenia, anorexia,malaise, and muscle aches in a subject can be determined by a medicalprofessional through the physical examination of the subject and/orinterviewing the subject (e.g., using a survey).

Also provided are methods of changing the adverse effects of treatmentof a subject with a FGFR-associated cancer, the method comprisingadministering to the subject a compound of Formula I or apharmaceutically acceptable salt or solvate thereof; and reducing a doseof a FGFR1 inhibitor administered to the subject, not administering aFGFR1 inhibitor to the subject, or ceasing to administer a FGFR1inhibitor to the subject. In some embodiments, the FGFR1 inhibitor isselected from the group consisting of brivanib, dovitinib, erdafitinib,nintedanib, orantinib, pemigatinib, ponatinib, rogaratinib, sulfatinib,ARQ-087, ASP5878, AZD4547, BGJ398, Debio 1347, E7090, HMPL-453,INCB054828, MAX-40279, PRN1371, and TAS-120. In some embodiments, theadverse effects can include one or more of: anorexia, asthenia,constipation, decreased appetite, diarrhea, dry mouth, elevatedphosphate level (e.g., hyperphosphatemia), fatigue, liver enzymeabnormalities, malaise, muscle aches, nail changes, nausea, soft tissuecalcification, and stomatitis. In some embodiments, the FGFR1 inhibitorhas an FGFR1 activity of less than 50 nM in an in vitro FGFR1 kinaseassay.

Also provided are methods of decreasing the number of the adverseeffects of treatment of a subject with a FGFR-associated cancer, themethod comprising administering to the subject a compound of Formula Ior a pharmaceutically acceptable salt or solvate thereof; and reducing adose of a FGFR1 inhibitor administered to the subject, not administeringa FGFR1 inhibitor to the subject, or ceasing to administer a FGFR1inhibitor to the subject. In some embodiments, the FGFR1 inhibitor isselected from the group consisting of brivanib, dovitinib, erdafitinib,nintedanib, orantinib, pernigatinib, ponatinib, rogaratinib, sulfatinib,ARQ-087, ASP5878, AZD4547, BGJ398, Debio 1347, E7090, HMPL-453,INCB054828, MAX-40279, PRN1371, and TAS-120. In some embodiments, theadverse effects can include one or more of: anorexia, asthenia,constipation, decreased appetite, diarrhea, dry mouth, elevatedphosphate level (e.g., hyperphosphatemia), fatigue, liver enzymeabnormalities, malaise, muscle aches, nail changes, nausea, soft tissuecalcification, and stomatitis. In some embodiments, the FGFR1 inhibitorhas an FGFR1 activity of less than 50 nM in an in vitro FGFR1 kinaseassay.

Also provided are methods of decreasing the severity of the adverseeffects of treatment of a subject with a FGFR-associated cancer, themethod comprising administering to the subject a compound of Formula Ior a pharmaceutically acceptable salt or solvate thereof; and reducing adose of a FGFR1 inhibitor administered to the subject, not administeringa FGFR1 inhibitor to the subject, or ceasing to administer a FGFR1inhibitor to the subject. In some embodiments, the FGFR1 inhibitor isselected from the group consisting of brivanib, dovitinib, erdafitinib,nintedanib, orantinib, pemigatinib, ponatinib, rogaratinib, sulfatinib,ARQ-087, ASP5878, AZD4547, BGJ398, Debio 1347, E7090, HMPL-453,INCB054828, MAX-40279, PRN1371, and TAS-120. In some embodiments, theadverse effects can include one or more of: anorexia, asthenia,constipation, decreased appetite, diarrhea, dry mouth, elevatedphosphate level (e.g., hyperphosphatemia), fatigue, liver enzymeabnormalities, malaise, muscle aches, nail changes, nausea, soft tissuecalcification, and stomatitis. In some embodiments, the FGFR1 inhibitorhas an FGFR1 activity of less than 50 nM in an in vitro FGFR1 kinaseassay.

Also provided are methods of preventing one or more adverse effects oftreatment of a subject with a FGFR-associated cancer, the methodcomprising administering to the subject a compound of Formula I or apharmaceutically acceptable salt or solvate thereof; and reducing a doseof a FGFR1 inhibitor administered to the subject, not administering aFGFR1 inhibitor to the subject, or ceasing to administer a FGFR1inhibitor to the subject. In some embodiments, the FGFR1 inhibitor isselected from the group consisting of brivanib, dovitinib, erdafitinib,nintedanib, orantinib, pemigatinib, ponatinib, rogaratinib, sulfatinib,ARQ-087, ASP5878, AZD4547, BGJ398, Debio 1347, E7090, HMPL-453,INCB054828, MAX-40279, PRN1371, and TAS-120. In some embodiments, theadverse effects can include one or more of: anorexia, asthenia,constipation, decreased appetite, diarrhea, dry mouth, elevatedphosphate level (e.g., hyperphosphatemia), fatigue, liver enzymeabnormalities, malaise, muscle aches, nail changes, nausea, soft tissuecalcification, and stomatitis. In some embodiments, the FGFR1 inhibitorhas an FGFR1 activity of less than 50 nM in an in vitro FGFR1 kinaseassay.

Also provided are methods of treating the adverse effects of treatmentof a subject with a FGFR-associated cancer, the method comprisingadministering to the subject a compound of Formula I or apharmaceutically acceptable salt or solvate thereof; and reducing a doseof a FGFR1 inhibitor administered to the subject, not administering aFGFR1 inhibitor to the subject, or ceasing to administer a FGFR1inhibitor to the subject. In some embodiments, the FGFR1 inhibitor isselected from the group consisting of brivanib, dovitinib, erdafitinib,nintedanib, orantinib, pemigatinib, ponatinib, rogaratinib, sulfatinib,ARQ-087, ASP5878, AZD4547, BGJ398, Debio 1347, E7090, HMPL-453,INCB054828, MAX-40279, PRN1371, and TAS-120. In some embodiments, theadverse effects can include one or more of: anorexia, asthenia,constipation, decreased appetite, diarrhea, dry mouth, elevatedphosphate level (e.g., hyperphosphatemia), fatigue, liver enzymeabnormalities, malaise, muscle aches, nail changes, nausea, soft tissuecalcification, and stomatitis. In some embodiments, the FGFR1 inhibitorhas an FGFR1 activity of less than 50 nM in an in vitro FGFR1 kinaseassay.

Also provided is a method for inhibiting FGFR kinase activity in a cell,comprising contacting the cell with a compound of Formula I. In someembodiments, the contacting is in vitro. In some embodiments, thecontacting is in vivo. In some embodiments, the contacting is in vivo,wherein the method comprises administering an effective amount of acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof to a subject having a cell having FGFR kinase activity. In someembodiments, the cell is a cancer cell. In some embodiments, the cancercell is any cancer as described herein. In some embodiments, the cancercell is a FGFR-associated cancer cell. In some embodiments, the cell isa bladder cancer cell.

Also provided is a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof for use in the inhibition of FGFR1,FGFR2, FGFR2, and/or FGFR4.

Also provided is the use of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof in the manufactureof a medicament for the inhibition of activity of FGFR1, FGFR2, FGFR3,or FGFR4.

Also provided is a method for inhibiting FGFR kinase activity in amammalian cell, comprising contacting the cell with a compound ofFormula I. In some embodiments, the contacting is in vitro. In someembodiments, the contacting is in vivo. In some embodiments, thecontacting is in vivo, wherein the method comprises administering aneffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof to a mammal having a cell having FGFRkinase activity. In some embodiments, the mammalian cell is a mammaliancancer cell. In some embodiments, the mammalian cancer cell is anycancer as described herein. In some embodiments, the mammalian cancercell is a FGFR-associated cancer cell. In some embodiments, themammalian cell is a bladder cancer cell.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” a FGFR kinase with a compound provided hereinincludes the administration of a compound provided herein to anindividual or subject, such as a human, having a FGFR kinase, as wellas, for example, introducing a compound provided herein into a samplecontaining a cellular or purified preparation containing the FGFRkinase.

Also provided herein is a method of inhibiting cell proliferation, invitro or in vivo, the method comprising contacting a cell with aneffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof, or a pharmaceutical compositionthereof as defined herein.

The phrase “effective amount” means an amount of compound that, whenadministered to a subject in need of such treatment, is sufficient to(i) treat a FGFR kinase-associated disease or disorder, (ii) attenuate,ameliorate, or eliminate one or more symptoms of the particular disease,condition, or disorder, or (iii) delay the onset of one or more symptomsof the particular disease, condition, or disorder described herein. Theamount of a compound (e.g., a compound of Formula I) that willcorrespond to such an amount will vary depending upon factors such asthe particular compound, disease condition and its severity, theidentity (e.g., weight) of the subject in need of treatment, but cannevertheless be routinely determined by one skilled in the art.

FGFR-associated diseases and disorders can include diseases anddisorders that are not cancer. Accordingly, provided herein are methodstreating a subject, the method comprising administering atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof, to a subject havinga clinical record that indicates that the subject has a dysregulation ofa FGFR gene, a FGFR kinase, or expression or activity or level of any ofthe same.

FGF/FGFR signaling plays a key role in development, including inorganogensesis, skeletal development, and neuronal development. See, forexample, Kelleher et al, Carcinogenesis 34(2):2198-2205, 2013; Su etal., Bone Res. 2:14003, 2014; McDonnel et al., Hum Mol Genet,24(R1):R60-6,2015; and Ornitz and Itoh, Wiley Interdiscip Rev Dev Bio4(3):215-266, 2015.

Non-limiting examples of FGFR-associated diseases and disorders includeAcanthosis nigricans, Achondroplasia, Apert syndrome, Beare-Stevensonsyndrome (BSS), Camptodactyly, tall stature, and hearing loss syndrome(CATSHL) syndrome, cleft lip and palate, congenital heart disease (e.g.,associated with ambiguous genitalia), craniosynostosis, Crouzonsyndrome, ectrodactyly, encephalocraniocutaneous lipomatosis, Hartsfieldsyndrome, hypochondroplasia, hypogonadoropic hypogonadism (e.g.,hypogonadotropic hypogonadism 2 with or without anosmia, Kallmansyndrome), ichthyosis vulgaris and/or atopic dermatitis, Jackson-Weisssyndrome, lethal pulmonary acinar dysplasia, microphthalmia, Muenkecoronal craniosynostosis, osteoglophonic dysplasia, Pfeiffer syndrome,seborrheic keratosis, syndactyly, thanatophoric dysplasia (e.g., type Ior type II), trigonocephaly 1 (also called metopic craniosynostosis),and tumor-induced osteomalacia. Non-limiting examples ofFGFR1-associated diseases and disorders include congenital heart disease(e.g., associated with ambiguous genitalia), craniosynostosis,encephalocraniocutaneous lipomatosis, Hartsfield syndrome,hypogonadoropic hypogonadism (e.g., hypogonadotropic hypogonadism 2 withor without anosmia, Kallman syndrome), ichthyosis vulgaris and/or atopicdermatitis, Jackson-Weiss syndrome, osteoglophonic dysplasia, Pfeiffersyndrome, trigonocephaly 1 (also called metopic craniosynostosis), andtumor-induced osteomalacia. Non-limiting examples of FGFR2-associateddiseases and disorders include Apert syndrome, Beare-Stevenson syndrome(BSS), Crouzon syndrome, ectrodactyly, Jackson-Weiss syndrome, lethalpulmonary acinar dysplasia, Pfeiffer syndrome, and syndactyly.Non-limiting examples of FGFR3-associated diseases and disorders includeacanthosis nigricans, achondroplasia, Camptodactyly, tall stature, andhearing loss syndrome (CATSHL) syndrome, cleft lip and palate,craniosynostosis, hypochondroplasia, microphthalmia, Muenke coronalcraniosynostosis, seborrheic keratosis, and thanatophoric dysplasia(e.g., type I or type II). Other non-limiting examples ofFGFR-associated diseases and disorders can be found, for example, inTable BD.

Accordingly, provided herein are methods for treating a subjectdiagnosed with (or identified as having) any of the FGFR-associateddiseases or disorders in Table BD (e.g., achondroplasia,hypochondroplasia, or thanatophoric dysplasia) that includeadministering to the subject a therapeutically effective amount of acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof. Also provided herein are methods for treating a subjectidentified or diagnosed as having any of the FGFR-associated diseases ordisorders in Table BD (e.g., achondroplasia, hypochondroplasia, orthanatophoric dysplasia) that include administering to the subject atherapeutically effective amount of a compound of Formula I orpharmaceutically acceptable salt or solvate thereof. For example, theFGFR-associated disease or disorder can be any of the FGFR-associateddiseases or disorders in Table BD (e.g., achondroplasia,hypochondroplasia, or thanatophoric dysplasia) that includes one or moreFGFR inhibitor resistance mutations.

Also provided are methods for treating a FGFR-associated disease ordisorder (e.g., a FGFR-associated disease or disorder that is not acancer) in a subject in need thereof, the method comprising: (a)detecting any of the FGFR-associated diseases or disorders in Table BD(e.g., achondroplasia, hypochondroplasia, or thanatophoric dysplasia) inthe subject; and (b) administering to the subject a therapeuticallyeffective amount of a compound of Formula I or pharmaceuticallyacceptable salt or solvate thereof. Some embodiments of these methodsfurther include administering to the subject an additional therapy ortherapeutic agent (e.g., a second FGFR inhibitor, a second compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof, animmunotherapy, a guanylyl cyclase B activator, a growth hormone, or anatriuretic peptide precursor C (CNP) agonist). In some embodiments, thesubject was previously treated with a first FGFR inhibitor or previouslytreated with another therapy or therapeutic agent. In some embodiments,the subject is determined to have any of the FGFR-associated diseases ordisorders in Table BD (e.g., achondroplasia, hypochondroplasia, orthanatophoric dysplasia) through the use of a regulatoryagency-approved, e.g., FDA-approved test or assay for identifyingdysregulation of a FGFR gene, a FGFR kinase, or expression or activityor level of any of the same, in a subject or a biopsy sample from thesubject or by performing any of the non-limiting examples of assaysdescribed herein. In some embodiments, the test or assay is provided asa kit. For example, the FGFR-associated disease or disorder can be anyof the FGFR-associated diseases or disorders in Table BD (e.g.,achondroplasia, hypochondroplasia, or thanatophoric dysplasia) thatincludes one or more FGFR mutations.

Also provided are methods of treating a subject that include performingan assay on a sample obtained from a subject to determine whether thesubject has a dysregulation of a FGFR gene, a FGFR kinase, or expressionor activity or level of any of the same, and administering (e.g.,specifically or selectively administering) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof to the subject determined to have a dysregulation ofa FGFR gene, a FGFR kinase, or expression or activity or level of any ofthe same. Some embodiments of these methods further includeadministering to the subject an additional therapy or therapeutic agent(e.g., a second FGFR inhibitor, a second compound of Formula I or apharmaceutically acceptable salt or solvate thereof, an immunotherapy, aguanylyl cyclase B activator, a growth hormone, or a natriuretic peptideprecursor C (CNP) agonist). In some embodiments of these methods, thesubject was previously treated with a first FGFR inhibitor or previouslytreated with another therapy or therapeutic agent. In some embodiments,the subject is a subject suspected of having a FGFR-associated diseaseor disorder, a subject presenting with one or more symptoms of aFGFR-associated disease or disorder. In some embodiments, the assayutilizes next generation sequencing, pyrosequencing,immunohistochemistry, or break apart FISH analysis. In some embodiments,the assay is a regulatory agency-approved assay, e.g., FDA-approved kit.In some embodiments, the assay is a liquid biopsy. Additional,non-limiting assays that may be used in these methods are describedherein. Additional assays are also known in the art. In someembodiments, the dysregulation of a FGFR gene, a FGFR kinase, orexpression or activity or level of any of the same includes one or moreFGFR mutations (e.g., any of the mutations in Table BD).

In some embodiments, provided herein are methods for treating aFGFR-associated disease or disorder (e.g., a FGFR-associated disease ordisorder that is not a cancer) in a subject in need of such treatment,the method comprising a) detecting a dysregulation of a FGFR gene, aFGFR kinase, or the expression or activity or level of any of the samein a sample from the subject; and b) administering a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof. In some embodiments, thedysregulation of a FGFR gene, a FGFR kinase, or the expression oractivity or level of any of the same includes one or more FGFR kinaseprotein point mutations/insertions/deletions. Non-limiting examples ofFGFR kinase protein point mutations/insertions/deletions are describedin Table BD. In some embodiments, the FGFR kinase protein pointmutations/insertions/deletions are selected from the group consisting ofpoint mutations/insertions/deletions corresponding to V561M in SEQ IDNO. 1, V564I or V564F in SEQ ID NO. 3, or V555M in SEQ ID NO. 5.

Also provided is a compound of Formula I or pharmaceutically acceptablesalt or solvate thereof for use in treating any of the FGFR-associateddiseases or disorders in Table BD (e.g., achondroplasia,hypochondroplasia, or thanatophoric dysplasia) in a subject identifiedor diagnosed as having any of the FGFR-associated diseases or disordersin Table BD (e.g., achondroplasia, hypochondroplasia, or thanatophoricdysplasia) through a step of performing an assay (e.g., an in vitroassay) on a sample obtained from the subject to determine whether thesubject has a dysregulation of a FGFR gene, a FGFR kinase, or expressionor activity or level of any of the same, where the presence of adysregulation of a FGFR gene, a FGFR kinase, or expression or activityor level of any of the same, identifies that the subject has aFGFR-associated disease or disorder. Also provided is the use of acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof for the manufacture of a medicament for treating any of theFGFR-associated diseases or disorders in Table BD (e.g., achondroplasia,hypochondroplasia, or thanatophoric dysplasia) in a subject identifiedor diagnosed as having any of the FGFR-associated diseases or disordersin Table BD (e.g., achondroplasia, hypochondroplasia, or thanatophoricdysplasia) through a step of performing an assay on a sample obtainedfrom the subject to determine whether the subject has a dysregulation ofa FGFR gene, a FGFR kinase, or expression or activity or level of any ofthe same where the presence of dysregulation of a FGFR gene, a FGFRkinase, or expression or activity or level of any of the same,identifies that the subject has a FGFR-associated disease or disorder.Some embodiments of any of the methods or uses described herein furtherinclude recording in the subject's clinical record (e.g., a computerreadable medium) that the subject is determined to have a dysregulationof a FGFR gene, a FGFR kinase, or expression or activity or level of anyof the same, through the performance of the assay, should beadministered a compound of Formula I or pharmaceutically acceptable saltor solvate thereof. In some embodiments, the assay utilizes nextgeneration sequencing, pyrosequencing, immunohistochemistry, or breakapart FISH analysis. In some embodiments, the assay is a regulatoryagency-approved assay, e.g., FDA-approved kit. In some embodiments, theassay is a liquid biopsy.

Also provided is a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof, for use in the treatment of any ofthe FGFR-associated diseases or disorders in Table BD (e.g.,achondroplasia, hypochondroplasia, or thanatophoric dysplasia) in asubject in need thereof or a subject identified or diagnosed as having aFGFR-associated disease or disorder (e.g., a FGFR-associated disease ordisorder that is not a cancer). Also provided is the use of a compoundof Formula I or a pharmaceutically acceptable salt or solvate thereoffor the manufacture of a medicament for treating any of theFGFR-associated diseases or disorders in Table BD (e.g., achondroplasia,hypochondroplasia, or thanatophoric dysplasia) in a subject identifiedor diagnosed as having a FGFR-associated disease or disorder. In someembodiments, the FGFR-associated disease or disorder is, for example,any of the FGFR-associated diseases or disorders in Table BD (e.g.,achondroplasia, hypochondroplasia, or thanatophoric dysplasia) havingone or more FGFR mutation (e.g., any of the mutations in Table BD). Insome embodiments, a subject is identified or diagnosed as having any ofthe FGFR-associated diseases or disorders in Table BD (e.g.,achondroplasia, hypochondroplasia, or thanatophoric dysplasia) throughthe use of a regulatory agency-approved, e.g., FDA-approved, kit foridentifying dysregulation of a FGFR gene, a FGFR kinase, or expressionor activity or level of any of the same, in a subject or a biopsy samplefrom the sample. As provided herein, any of the FGFR-associated diseasesor disorders in Table BD (e.g., achondroplasia, hypochondroplasia, orthanatophoric dysplasia) includes those described herein and known inthe art.

FGF/FGFR signaling is also involved in angiogenesis. See, for example,Carmeliet and Jain, Nature 473(7347):298-307,2011; Presta et al.,Cytokine Growth Factor Rev., 16(2):159-178,2005; and Cross andClaesson-Welsh, Trends Parmacol Sci., 22(4): 201-207,2001. Aberrantangiogenesis can be present in cancer, or in other diseases orconditions, such as ocular diseases or conditions (e.g., maculardegeneration (e.g., exudative macular degeneration), diabeticretinopathy (e.g., proliferative diabetic retinopathy)) or inflammatorydiseases or conditions (e.g., rheumatoid arthritis). In someembodiments, an angiogenesis-related disorder is selected from the groupconsisting of macular degeneration, diabetic retinopathy, ischemicretinopathy, retinopathy of prematurity, neovascular glaucoma, iritisrubeosis, corneal neovascularization, cyclitis, sickle cell retinopathy,pterygium, and rheumatoid arthritis.

Accordingly, provided herein are methods for treating a subjectdiagnosed with (or identified as having) an angiogenesis-relateddisorder that include administering to the subject a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof. Also provided herein are methods fortreating a subject identified or diagnosed as having anangiogenesis-related disorder that include administering to the subjecta therapeutically effective amount of a compound of Formula I orpharmaceutically acceptable salt or solvate thereof. In someembodiments, the subject that has been identified or diagnosed as havingan angiogenesis-related disorder through the use of a regulatoryagency-approved, e.g., FDA-approved test or assay, in a subject or abiopsy sample from the subject or by performing any of the non-limitingexamples of assays described herein. In some embodiments, the test orassay is provided as a kit. For example, the angiogenesis-relateddisorder can be a FGFR-associated disease or disorder that includes oneor more FGFR inhibitor resistance mutations.

Also provided are methods for treating an angiogenesis-related disorderin a subject in need thereof, the method comprising: (a) detecting anangiogenesis-related disorder in the subject; and (b) administering tothe subject a therapeutically effective amount of a compound of FormulaI or pharmaceutically acceptable salt or solvate thereof. Someembodiments of these methods further include administering to thesubject an additional therapy or therapeutic agent (e.g., a second FGFRinhibitor, a second compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof, or an immunotherapy). Someembodiments of these methods further include administering to thesubject an additional therapy or therapeutic agent. In some embodiments,the subject was previously treated with a first FGFR inhibitor orpreviously treated with another therapy or therapeutic therapy. In someembodiments, the subject is determined to have an angiogenesis-relateddisorder through the use of a regulatory agency-approved, e.g.,FDA-approved test or assay, in a subject or a biopsy sample from thesubject or by performing any of the non-limiting examples of assaysdescribed herein. In some embodiments, the test or assay is provided asa kit. For example, the angiogenesis-related disorder can be aFGFR-associated disease or disorder that includes one or more FGFRmutations.

Also provided are methods of treating a subject that include performingan assay on a sample obtained from a subject to determine whether thesubject has an angiogenesis-related disorder, and administering (e.g.,specifically or selectively administering) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof to the subject determined to have anangiogenesis-related disorder. Some embodiments of these methods furtherinclude administering to the subject an additional therapy ortherapeutic agent (e.g., a second FGFR inhibitor, a second compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof, orimmunotherapy). In some embodiments of these methods, the subject waspreviously treated with a first FGFR inhibitor or previously treatedwith another therapy or therapeutic agent. In some embodiments, thesubject is a subject suspected of having an angiogenesis-relateddisorder, or a subject presenting with one or more symptoms of anangiogenesis-related disorder. In some embodiments, the assay utilizesnext generation sequencing, pyrosequencing, immunohistochemistry, orbreak apart FISH analysis. In some embodiments, the assay is aregulatory agency-approved assay, e.g., FDA-approved kit. In someembodiments, the assay is a liquid biopsy. Additional, non-limitingassays that may be used in these methods are described herein.Additional assays are also known in the art. In some embodiments,angiogenesis-related disorder includes one or more FGFR mutations (e.g.,any of the mutations in Table BC or Table BD).

In some embodiments, provided herein are methods for treating anangiogenesis-related disorder in a subject in need of such treatment,the method comprising a) detecting an angiogenesis-related disorder in asample from the subject; and b) administering a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof. In some embodiments, theangiogenesis-related disorder is a dysregulation of a FGFR gene, a FGFRkinase, or the expression or activity or level of any of the same andincludes one or more FGFR kinase protein pointmutations/insertions/deletions. Non-limiting examples of FGFR kinaseprotein point mutations/insertions/deletions are described in Table BCand Table BD. In some embodiments, the FGFR kinase protein pointmutations/insertions/deletions are selected from the group consisting ofpoint mutations/insertions/deletions corresponding to V561M in SEQ IDNO. 1, V564I or V564F in SEQ ID NO. 3, or V555M in SEQ ID NO. 5.

In some embodiments of any of the methods disclosed herein, treatingwith a compound of Formula I can result in a decrease in the diameter ofa blood vessel and/or a decrease in the number of blood vessels in atissue in need of a reduction in the number of blood vessels (e.g., ascompared to the diameter of the blood vessel and/or the number of bloodvessels in the tissue in the patient prior to treatment). In someexamples the methods can result in, e.g., a decrease in the diameter ofa blood vessel of about 1% to about 80%, 75%, 70%, 65%, 60%, 55%, 50%,45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5%; about 2% to about 80%,75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or5%; about 3% to about 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%,30%, 25%, 20%, 15%, 10%, or 5%; about 5% to about 80%, 75%, 70%, 65%,60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10%; about 10% toabout 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%,or 15%; about 15% to about 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%,35%, 30%, 25%, or 20%; about 20% to about 80%, 75%, 70%, 65%, 60%, 55%,50%, 45%, 40%, 35%, 30%, or 25%; about 25% to about 80%, 75%, 70%, 65%,60%, 55%, 50%, 45%, 40%, 35%, or 30%; about 30% to about 80%, 75%, 70%,65%, 60%, 55%, 50%, 45%, 40%, or 35%; about 35% to about 80%, 75%, 70%,65%, 60%, 55%, 50%, 45%, or 40%; about 40% to about 80%, 75%, 70%, 65%,60%, 55%, 50%, or 45%; about 45% to about 80%, 75%, 70%, 65%, 60%, 55%,or 50%; about 50% to about 80%, 75%, 70%, 65%, 60%, or 55%; about 55% toabout 80%, 75%, 70%, 65%, or 60%; about 60% to about 80%, 75%, 70%, or65%; about 65% to about 80%, 75%, or 70%; about 70% to about 80% or 75%;or about 75% to about 80% (e.g., as compared to the diameter of theblood vessel in the patient prior to treatment). In some examples themethods can result in, e.g., a decrease in the number of blood vesselsin a tissue in need of a reduction in the number of blood vessels ofabout 5% to about 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%,25%, 20%, 15%, or 10%; about 10% to about 80%, 75%, 70%, 65%, 60%, 55%,50%, 45%, 40%, 35%, 30%, 25%, 20%, or 15%; about 15% to about 80%, 75%,70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, or 20%; about 20% orabout 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, or 25%;about 25% to about 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, or30%; about 30% to about 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, or35%; about 35% to about 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40%;about 40% to about 80%, 75%, 70%, 65%, 60%, 55%, 50%, or 45%; about 45%to about 80%, 75%, 70%, 65%, 60%, 55%, or 50%; about 50% to about 80%,75%, 70%, 65%, 60%, or 55%; about 55% to about 80%, 75%, 70%, 65%, or60%; about 60% to about 80%, 75%, 70%, or 65%; about 65% to about 80%,75%, or 70%; about 70% to about 80% or 75%; or about 75% to about 80%(e.g., as compared to the diameter of the blood vessel and/or the numberof blood vessels in the tissue in the patient prior to treatment). Thesemethods can also result in a decrease in the rate of formation of newblood vessels in a tissue in need thereof in a patient having anangiogenesis-related disorder (e.g., as compared to the rate offormation of new blood vessels in the tissue in the patient prior totreatment, or the rate of formation of new blood vessels in a patient ora population of patients having the same or similar angiogenesis-relateddisorder). The decrease in the rate of formation of a new blood vesselsin a tissue in need thereof in a patient having an angiogenesis-relateddisorder can be about 1% to about 100%, 95%, 90%, 85%, 80%, 75%, 70%,65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5%; about5% to about 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%,40%, 35%, 30%, 25%, 20%, 15%, or 10%; about 10% to about 100%, 95%, 90%,85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, or15%; about 15% to 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%,50%, 45%, 40%, 35%, 30%, 25%, or 20%; about 20% to 100%, 95%, 90%, 85%,80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, or 25%; about 25%to 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%,35%, or 30%; about 30% to 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%,55%, 50%, 45%, 40%, or 35%; about 35% to 100%, 95%, 90%, 85%, 80%, 75%,70%, 65%, 60%, 55%, 50%, 45%, or 40%; about 40% to 100%, 95%, 90%, 85%,80%, 75%, 70%, 65%, 60%, 55%, 50%, or 45%; about 45% to 100%, 95%, 90%,85%, 80%, 75%, 70%, 65%, 60%, 55%, or 50%; about 50% to 100%, 95%, 90%,85%, 80%, 75%, 70%, 65%, 60%, or 55%; about 55% to 100%, 95%, 90%, 85%,80%, 75%, 70%, 65%, or 60%; about 60% to 100%, 95%, 90%, 85%, 80%, 75%,70%, or 65%; about 65% to 100%, 95%, 90%, 85%, 80%, 75%, or 70%; about70% to 100%, 95%, 90%, 85%, 80%, or 75%; about 75% to 100%, 95%, 90%,85%, or 80%; about 80% to 100%, 95%, 90%, or 85%; about 85% to 100%,95%, or 90%; about 90% to about 100% or 95%; or about 95% to about 100%(e.g., as compared to the rate of formation of new blood vessels in thetissue in the patient prior to treatment, or the rate of formation ofnew blood vessels in a patient or a population of patients having thesame or similar angiogenesis-related disorder).

Also provided is the use of a compound of Formula I or apharmaceutically acceptable salt or solvent thereof for treating anangiogenesis-related disorder in a patient. Also provided is the use ofa compound of Formula I or a pharmaceutically acceptable salt or solvatethereof in the manufacture of a medicament for treating anangiogenesis-related disorder in a patient.

Also provided is a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof for use in treating anangiogenesis-related disorder in a subject identified or diagnosed ashaving an angiogenesis-related disorder through a step of performing anassay (e.g., an in vitro assay) on a sample obtained from the subject.Some embodiments of any of the methods or uses described herein furtherinclude recording in the subject's clinical record (e.g., a computerreadable medium) that the subject is determined to have anangiogenesis-related disorder and should be administered a compound ofFormula I or pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the assay utilizes next generation sequencing,pyrosequencing, immunohistochemistry, or break apart FISH analysis. Insome embodiments, the assay is a regulatory agency-approved assay, e.g.,FDA-approved kit. In some embodiments, the assay is a liquid biopsy. Insome embodiments, the angiogenesis-related disorder is a dysregulationof a FGFR gene, a FGFR kinase, or expression or activity or level of anyof the same includes one or more FGFR mutation (e.g., any of themutations in Table BC or Table BD).

Also provided is a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof, for use in the treatment of anangiogenesis-related disorder in a subject in need thereof or a subjectidentified or diagnosed as having an angiogenesis-related disorder. Alsoprovided is the use of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof for the manufacture of a medicamentfor treating an angiogenesis-related disorder in a subject identified ordiagnosed as having an angiogenesis-related disorder. In someembodiments, the angiogenesis-related disorder is, for example, anangiogenesis-related disorder having one or more FGFR mutations (e.g.,any of the mutations in Table BC or Table BD). In some embodiments, asubject is identified or diagnosed as having an angiogenesis-relateddisorder through the use of a regulatory agency-approved, e.g.,FDA-approved, kit for identifying dysregulation of a FGFR gene, a FGFRkinase, or expression or activity or level of any of the same, in asubject or a biopsy sample from the sample. As provided herein, anangiogenesis-related disorder includes those described herein and knownin the art.

Also provided herein are methods for treating a disease involvingangiogenesis and/or neovascularization, comprising administering to asubject in need thereof, a therapeutically effective amount of acompound of Formula I.

Also provided herein are methods for inhibiting angiogenesis in a tumor,which comprises contacting the tumor with a compound of Formula I.

When employed as pharmaceuticals, the compounds of Formula I can beadministered in the form of pharmaceutical compositions. Thesecompositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral or parenteral. Oral administrationcan include a dosage form formulated for once-daily or twice-daily (BID)administration. Parenteral administration includes intravenous,intraarterial, subcutaneous, intraperitoneal intramuscular or injectionor infusion; or intracranial, e.g., intrathecal or intraventricular,administration. Parenteral administration can be in the form of a singlebolus dose, or may be, for example, by a continuous perfusion pump.Pharmaceutical compositions and formulations for topical administrationmay include transdermal patches, ointments, lotions, creams, gels,drops, suppositories, sprays, liquids and powders. Conventionalpharmaceutical carriers, aqueous, powder or oily bases, thickeners andthe like may be necessary or desirable.

Also provided herein are pharmaceutical compositions that contain, asthe active ingredient, a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof, in combination with one or morepharmaceutically accepTable BCarriers (excipients). In some embodiments,the composition is suitable for topical administration. In making thecompositions provided herein, the active ingredient is typically mixedwith an excipient, diluted by an excipient or enclosed within such acarrier in the form of, for example, a capsule, sachet, paper, or othercontainer. When the excipient serves as a diluent, it can be a solid,semi-solid, or liquid material, which acts as a vehicle, carrier ormedium for the active ingredient. Thus, the compositions can be in theform of tablets, pills, powders, lozenges, sachets, cachets, elixirs,suspensions, emulsions, solutions, syrups, aerosols (as a solid or in aliquid medium), ointments containing, for example, up to 10% by weightof the active compound, soft and hard gelatin capsules, suppositories,sterile injectable solutions, and sterile packaged powders. In someembodiments, the composition is formulated for oral administration. Insome embodiments, the composition is formulated as a tablet or capsule.

The compositions comprising a compound of Formula I or apharmaceutically acceptable salt or solvate thereof can be formulated ina unit dosage form, each dosage containing from about 5 to about 1,000mg (1 g), more usually about 100 mg to about 500 mg, of the activeingredient. The term “unit dosage form” refers to physically discreteunits suiTable BAs unitary dosages for human subjects and othersubjects, each unit containing a predetermined quantity of activematerial (i.e., a compound of Formula I as provided herein) calculatedto produce the desired therapeutic effect, in association with asuitable pharmaceutical excipient.

In some embodiments, the compositions provided herein contain from about5 mg to about 50 mg of the active ingredient. One having ordinary skillin the art will appreciate that this embodies compounds or compositionscontaining about 5 mg to about 10 mg, about 10 mg to about 15 mg, about15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40mg to about 45 mg, or about 45 mg to about 50 mg of the activeingredient.

In some embodiments, the compositions provided herein contain from about50 mg to about 500 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compounds orcompositions containing about 50 mg to about 100 mg, about 100 mg toabout 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250mg, about 250 mg to about 300 mg, about 350 mg to about 400 mg, or about450 mg to about 500 mg of the active ingredient.

In some embodiments, the compositions provided herein contain from about500 mg to about 1,000 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compounds orcompositions containing about 500 mg to about 550 mg, about 550 mg toabout 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg toabout 950 mg, or about 950 mg to about 1,000 mg of the activeingredient.

The active compound may be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual subject, the severity of thesubject's symptoms, and the like.

In some embodiments, the compounds provided herein can be administeredin an amount ranging from about 1 mg/kg to about 100 mg/kg. In someembodiments, the compound provided herein can be administered in anamount of about 1 mg/kg to about 20 mg/kg, about 5 mg/kg to about 50mg/kg, about 10 mg/kg to about 40 mg/kg, about 15 mg/kg to about 45mg/kg, about 20 mg/kg to about 60 mg/kg, or about 40 mg/kg to about 70mg/kg. For example, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg,about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85mg/kg, about 90 mg/kg, about 95 mg/kg, or about 100 mg/kg. In someembodiments, such administration can be once-daily or twice-daily (BID)administration.

Provided herein are pharmaceutical kits useful, for example, in thetreatment of FGFR-associated diseases or disorders, such as cancer orany of the FGFR-associated diseases in Table BD (e.g., achondroplasia,hypochondroplasia, or thanatophoric dysplasia), which include one ormore containers containing a pharmaceutical composition comprising atherapeutically effective amount of a compound provided herein. Suchkits can further include, if desired, one or more of variousconventional pharmaceutical kit components, such as, for example,containers with one or more pharmaceutically accepTable BCarriers,additional containers, etc., as will be readily apparent to thoseskilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

One skilled in the art will recognize that, both in vivo and in vitrotrials using suitable, known and generally accepted cell and/or animalmodels are predictive of the ability of a test compound to treat orprevent a given disorder.

One skilled in the art will further recognize that human clinical trialsincluding first-in-human, dose ranging and efficacy trials, in healthysubjects and/or those suffering from a given disorder, may be completedaccording to methods well known in the clinical and medical arts.

EXAMPLES

The following examples illustrate the invention.

Synthetic Intermediates

Intermediate P1

3-chloro-N-(3,5-dimethoxyphenyl)quinoxalin-6-amine

Step 1: Preparation of 7-((3,5-dimethoxyphenyl)amino)quinoxalin-2-ol. Asuspension of 7-bromoquinoxalin-2(1H)-one (2.26 g, 10.0 mmol),3,5-dimethoxyaniline (1.85 g, 12.1 mmol), NaOtBu (2.90 g, 30.1 mmol),BINAP (0.625 g, 1.00 mmol) and Pd(OAc)₂ (0.225 g, 1.00 mmol) in DME (35mL) was purged with Ar_((g)) for 10 min, then stirred for 16 h at 85° C.under an Ar_((g)) balloon. After cooling to ambient temperature, thereaction mixture was concentrated in vacuo. The resulting residue wassuspended in EtOAc (10 mL) and water (150 mL), then stirred for 30 min.The resulting suspension was filtered, and the solids collected werewashed sequentially with water (50 mL) and ACN (50 mL), then dried invacuo to yield the title compound (2.95 g, 98% yield). MS (apci)m/z=298.1 (M+H).

Step 2: Preparation of3-chloro-N-(3,5-dimethoxyphenyl)quinoxalin-6-amine. A suspension of7-((3,5-dimethoxyphenyl)amino)quinoxalin-2-ol (Step 1; 0.431 g, 1.45mmol) and phosphoryl trichloride (5.95 mL, 63.78 mmol) was stirred for 1h at 80° C. After cooling to ambient temperature, the reaction mixturewas concentrated in vacuo. The residue was diluted with DCM (50 mL), andstirred for 30 min at ambient temperature. The DCM mixture then wascarefully poured into 10% K₂CO_(3(aq)) (200 mL), and stirred for 30 minat ambient temperature. The resulting suspension was filtered through apad of Celite to remove solids, and the biphasic filtrate was separated.The organic layer was dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo. The crude product was purified by silica gelchromatography (using 20-80% EtOAc in Hexanes as the gradient eluent) toyield the title compound (0.135 g, 29% yield). MS (apci) m/z=316.0(M+H).

Intermediate R1

tert-butyl4-(6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate

Step 1: Preparation of tert-butyl4-(5-bromo-6-methylpyridin-2-yl)piperazine-1-carboxylate. A solution of5-bromo-2-chloro-6-methylpyridine (812.0 mg, 3.933 mmol) in DMSO (4.0mL) was treated with tert-butyl 1-piperazinecarboxylate (1465 mg, 7.866mmol) and DIEA (1370 μL, 7.866 mmol). The resulting mixture was stirredfor 16 h at 90° C. in a sealed tube. After cooling to ambienttemperature, the reaction mixture was diluted with water, and extractedwith EtOAc (2×). The combined organic extracts were washed successivelywith water (3×) and brine (1×), then sequentially dried over anhydrousNa₂SO_(4(s)), filtered, and concentrated in vacuo. The crude residue waspurified by silica gel chromatography (using 5-70% Hexanes-EtOAc as thegradient eluent) to afford the title compound (80.1 mg, 6% yield). MS(apci) m/z=358.1 (M+H).

Step 2: Preparation of tert-butyl4-(6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate.A solution of tert-butyl4-(5-bromo-6-methylpyridin-2-yl)piperazine-1-carboxylate (Step 1; 662.4mg, 1.859 mmol) in dioxane (18.6 mL, 0.1 M) was treated withbis(Pinacolato)diboron (519.4 mg, 2.045 mmol), PdCl₂(dppf).CH₂Cl₂ (151.8mg, 0.1859 mmol), and KOAC_((s)) (547.4 mg, 5.578 mmol). The resultingmixture was sparged with Ar_((g)) for 10 min, before sealing thereaction vessel. The mixture then was stirred overnight at 80° C. Aftercooling to ambient temperature, the reaction mixture was diluted withEtOAc, then washed successively with water (2×) and brine (1×). Theorganic extracts were dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (using 5-75% Hexanes-EtOAc as the gradient eluents) tocleanly provide the title compound (0.586 g, 78% yield). MS (apci)m/z=404.2 (M+H).

Intermediate R2

tert-butyl4-(4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate

Step 1: Preparation of tert-butyl4-(5-bromo-4-methylpyridin-2-yl)piperazine-1-carboxylate. A solution of5-bromo-2-fluoro-4-methylpyridine (910.3 mg, 4.791 mmol) in DMSO (4.8mL, 1.0 M) was treated with tert-butyl 1-piperazinecarboxylate (1785 mg,9.581 mmol) and DIEA (1669 μL, 9.581 mmol). The resulting mixture wasstirred for 16 h at 90° C. in a sealed tube. Subsequently, the mixturewas cooled to ambient temperature, diluted with water, and extractedwith EtOAc (2×). The combined organic extracts were washed successivelywith water (3×) and brine (1×), then dried over anhydrous Na₂SO_(4(s)),filtered, and concentrated in vacuo. The resulting residue was purifiedby silica gel chromatography (using 5-70% Hexanes-EtOAc as gradienteluent) to cleanly afford the title compound (1.09 g, 64%). MS (apci)m/z=358 (M+H).

Step 2: Preparation of tert-butyl4-(4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate.A solution of tert-butyl4-(5-bromo-4-methylpyridin-2-yl)piperazine-1-carboxylate (Step 1; 521.8mg, 1.465 mmol) in dioxane (7.3 mL, 0.2 M) was treated withbis(Pinacolato)diboron (446.3 mg, 1.758 mmol), PdCl₂(dppf).CH₂Cl₂ (119.6mg, 0.1465 mmol), and KOAC_((s)) (431.2 mg, 4.394 mmol). The resultingmixture was sparged with Ar_((g)) for 10 min, before sealing thereaction vessel. The mixture then was stirred for 3 d at 80° C. Aftercooling to ambient temperature, the reaction mixture was diluted withEtOAc then washed successively with water (2×) and brine (1×). Theorganic extracts were dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (using 0-100% Hexanes-EtOAc as the gradient eluent) tocleanly provide the title compound (0.377 g, 63% yield). MS (apci)m/z=404.3 (M+H).

Intermediate R3 and Intermediate R4

tert-butyl 4-(4-bromo-3-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate(Intermediate R3) and tert-butyl4-(4-bromo-5-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate(Intermediate R4)

A solution of 4-bromo-3-methylpyrazole (1.5 g, 9.32 mmol) in DMA (46.6mL) was treated sequentially with NaH (60 wt. % mineral oil dispersion;0.745 g, 18.6 mmol) and 4-methanesulfonyloxy-piperidine-1-carboxylicacid tert-butyl ester (3.90 g, 14.0 mmol). The reaction mixture wasstirred overnight at 70° C. After cooling to ambient temperature, thereaction mixture was diluted with water, and extracted with EtOAc (3×).The combined organic extracts were washed with water (2×) and brine(1×), then dried over anhydrous Na₂SO_(4(s)), filtered and concentratedin vacuo. The resulting oil was purified by silica gel chromatography(using 0-100% DCM-EtOAc as the gradient eluent) to separately afford thetitle compounds:

Intermediate R34-(4-bromo-3-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate wasobtained as the more polar product (1.7 g, 53% yield). ¹H NMR (400 MHz,d⁶-DMSO) δ 7.89 (s, 1H), 4.21 (m, 1H), 3.96 (m, 2H), 2.82 (m, 2H), 2.07(s, 3H), 1.90 (m, 2H), 1.68 (m, 2H), 1.37 (s, 9H).

Intermediate R4 tert-butyl4-(4-bromo-5-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate wasobtained as the less polar product (860 mg, 27% yield). ¹H NMR (400 MHz,d⁶-DMSO) δ 7.45 (s, 1H), 4.35 (m, 1H), 4.01 (m, 2H), 2.86 (m, 2H), 2.23(s, 3H), 1.75 (m, 4H), 1.38 (s, 9H).

Intermediate R5

(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-methyl-1H-pyrazol-4-yl)boronicacid

A cold (−78° C.) solution of tert-butyl4-(4-bromo-5-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate(Intermediate R4; 793.3 mg, 2.304 mmol) in THF (23 mL, 0.1 M) wastreated with n-BuLi (2.5 M in Hexanes; 1844 μL, 4.609 mmol), thenstirred for 30 min at −78° C. To this was added triisopropyl borate(1060 μL, 4.609 mmol), and the resulting mixture was warmed to 0° C.,and stirred for 1 h at 0° C. The reaction mixture then was quenched withwater, and extracted with EtOAc (2×). The combined organic extracts werewashed with brine (1×), dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo. The resulting oil was purified by silica gelchromatography (using 3:1 DCM:MeOH as the gradient eluent) to afford thetitle compound (0.305 g, 42% yield). MS (apci) m/z=310.2 (M+H).

Intermediate R6

(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)boronicacid

A cold (−78° C.) solution of tert-butyl4-(4-bromo-3-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate(Intermediate R3; 1.58 g, 4.590 mmol) in THF (46 mL, 0.1 M) was treatedwith n-BuLi (2.5 M in Hexanes; 2.2 mL, 5.508 mmol), then stirred for 30min at −78° C. To this was added triisopropyl borate (2.11 mL, 9.18mmol), and the resulting mixture was warmed to 0° C., and stirred for 1h at 0° C. The reaction mixture then was quenched with water andextracted with EtOAc (2×). The combined organic extracts were washedwith brine (1×), dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo. The resulting oil was purified by silica gelchromatography (using 1-30% MeOH in DCM as the gradient eluent) toafford the title compound (0.452 g, 32% yield). MS (apci) m/z=310.1(M+H).

Intermediate R7

tert-butyl4-(4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)piperidine-1-carboxylate

A solution of 4-bromo-3,5-dimethylpyrazole (3.00 g, 17.1 mmol) in DMF(100 mL) was treated sequentially with4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (5.75g, 20.6 mmol) and NaH (60 wt. % mineral oil dispersion; 1.03 g, 25.7mmol). The reaction mixture was stirred for 16 h at 70° C. overnight,before sequentially introducing additional NaH (60 wt. % mineral oildispersion; 1.03 g, 25.7 mmol) andmethanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (2.39g, 8.55 mmol). The resulting mixture was stirred for an additional 24 hat 70° C. After cooling to ambient temperature, the reaction mixture wastreated with water and extracted with EtOAc (2×). The combined organicextracts were washed successively with water (3×) and brine (1×), thendried over anhydrous Na₂SO_(4(s)), filtered, and concentrated in vacuo.The resulting residue was purified by silica gel chromatography (using10-50% EtOAc-Hexanes as the gradient eluent) to provide the titlecompound (5.72 g, 93% yield). MS (apci) m/z=358.1 (M+H).

Intermediate R8

(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3,5-dimethyl-1H-pyrazol-4-yl)boronicacid

A cold (−78° C.) solution of tert-butyl4-(4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)piperidine-1-carboxylate(Intermediate R7; 1.37 g, 3.82 mmol) in THF (38 mL, 0.1 M) was treatedwith n-BuLi (2.5 M in Hexanes; 1.84 mL, 4.59 mmol), then stirred for 30min at −78° C. To this was added triisopropyl borate (1.76 mL, 7.65mmol), and the resulting mixture was warmed to 0° C., and stirred for 1h at 0° C. The reaction mixture was quenched with water and extractedwith EtOAc (2×). The combined organic extracts were washed with brine(1×), dried over anhydrous Na₂SO_(4(s)), filtered and concentrated invacuo to provide the title compound which was used as it is withoutpurification (1.18 g, 40% pure, 38% yield). MS (apci) m/z=324.2 (M+H).

Intermediate P2

N-(3,5-dimethoxyphenyl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinoxalin-6-amine

Step 1: Preparation of tert-butyl4-(4-(7-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate.A solution of 3-chloro-N-(3,5-dimethoxyphenyl)quinoxalin-6-amine(Intermediate PI; 994 mg, 3.15 mmol) in 4:1 dioxane/water (32 mL) wastreated with tert-butyl4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate(1306 mg, 3.46 mmol), K₂CO_(3(s)) (1305 mg, 9.44 mmol), and Pd(PPh₃)₄(182 mg, 0.157 mmol). The reaction mixture was sparged with Ar_((g)) for10 min, and then stirred for 16 h at 80° C. under an atmosphere ofAr_((g)). The reaction mixture was cooled to ambient temperature,quenched with water and extracted with EtOAc (3×). The combined organicextracts were washed with water (2×) and brine (2×), then dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo. Theresulting residue was purified by silica gel chromatography (using50-100% EtOAc-Hexanes as the gradient eluent) to provide the titlecompound (1.67 g, 99% yield). MS (apci) m/z=531.2 (M+H).

Step 2: Preparation ofN-(3,5-dimethoxyphenyl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinoxalin-6-amine.A solution of tert-butyl4-(4-(7-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(step 1; 1670 mg, 3.147 mmol) in DCM (8 mL) was treated with TFA (4 mL),then stirred for 15 min at ambient temperature. The reaction mixture wasconcentrated in vacuo, quenched with saturated NaHCO_(3(aq)), andextracted with 4:1 DCM:iPrOH. The organic extracts were washed withbrine (2×), dried over anhydrous Na₂SO_(4(s)), filtered and concentratedin vacuo to provide the title compound (1.35 g, 99% yield). MS (apci)m/z=431.2 (M+H).

The compounds in Table CA¹ were prepared using a similar 2 step methodto that described in the synthesis ofN-(3,5-dimethoxyphenyl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinoxalin-6-amine(Intermediate P2), employing the following modifications: in Step 1,reactions were conducted at 80-90° C., using 1.5-3 equivalents of base(K₂CO_(3(s)) or Na₂CO_(3(s))), 0.05-0.1 equivalents of Pd(PPh₃)₄,solvent (4:1 dioxanes:water) concentration of 0.1-0.28 M and replacingboth the 3-chloro-N-(3,5-dimethoxyphenyl)quinoxalin-6-amine(Intermediate PI) and tert-Butyl4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylaterespectively with 1.0 equivalent of the appropriate Aryl Chloride coreand 1.0-1.5 equivalents of the appropriate boronic ester (or acid) fromTable CAM (or elsewhere in the intermediates section); and in Step 2,using DCM: TFA ratios of 1:1-2:1 and replacing the tert-butyl4-(4-(7-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Step 1) with the appropriate Boc-protected coupling product from Step 1in each. All reactions were monitored for completion by LCMS, and assuch reaction durations were adjusted accordingly. When necessary, titlecompounds (Step 1 and/or Step 2) were isolated from silica gelchromatographic purification using an appropriate gradient eluent or C18reverse phase chromatographic purification using an appropriate gradienteluent followed by a basic aqueous wash.

TABLE CA¹ Inter- MS mediate (apci) # Structure Chemical Name m/z P3

N-(3,5-dimethoxyphenyl)- 3-(6-(piperazin-1-yl)- pyridin-3-yl)quinoxalin-6-amine 443.2 (M + H) P4

N-(3,5-dimethoxyphenyl)- 3-(2-methyl-6-(piperazin-1-yl)pyridin-3-yl)quinox- alin-6-amine 457.2 (M + H) P5

N-(3,5-dimethoxyphenyl)- 3-(4-methyl-6-(piperazin-1-yl)pyridin-3-yl)quinox- alin-6-amine 457.2 (M + H) P6

3-(1-(azetidin-3-yl)-1H- pyrazol-4-yl)-N-(3,5- dimethoxyphenyl)quinox-alin-6-amine 403.2 (M + H) P7

N-(3,5-dimethoxyphenyl)- 3-(5-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)- quinoxalin-6-amine 445.2 (M + H) P8

(R)-N-(3,5-dimethoxy- phenyl)-3-(1-(pyrrolidin- 3-yl)-1H-pyrazol-4-yl)-quinoxalin-6-amine 417.2 (M + H) P9

N-(3,5-dimethoxyphenyl)- 3-(3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)- quinoxalin-6-amine 445.2 (M + H) P10

N-(3,5-dimethoxyphenyl)- 3-(3-(piperazin-1-yl)-phenyl)quinoxalin-6-amine 442.2 (M + H) P11

N-(3,5-dimethoxyphenyl)- 3-(3,5-dimethyl-1-piperi-din-4-yl)-1H-pyrazol-4- yl)quinoxalin-6-amine 459.2 (M + H)

TABLE CA¹i CAS#/ Intermediate # Structure Chemical Name 877399-74-1

tert-Butyl 4-[4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine- 1-carboxylate 496786-98-2

Tert-butyl 4-(5-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)-pyridin-2-yl)piperazine- 1-carboxylate Intermediate R1

tert-butyl 4-(6-methyl- 5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pipera- zine-1-carboxylate Intermediate R2

tert-butyl 4-(4-methyl- 5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pipera- zine-1-carboxylate 877399-35-4

tert-butyl 3-(4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine- 1-carboxylate Intermediate R5

(1-(1-(tert-butoxycar- bonyl)piperidin-4-yl)-5- methyl-1H-pyrazol-4-yl)boronic acid 1175273-52-5

tert-butyl (R)-3-(4- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)- pyrrolidine-1-carbox- ylate Intermediate R6

(1-(1-(tert-butoxycar- bonyl)piperidin-4-yl)-3- methyl-1H-pyrazol-4-yl)boronic acid 540752-87-2

tert-butyl 4-(3-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)-phenyl)piperazine-1- carboxylate Intermediate R8

(1-(1-(tert-butoxycar- bonyl)piperidin-4-yl)- 3,5-dimethyl-1H-pyrazol-4-yl)boronic acid

TABLE CBi CAS# Structure Chemical Name 142253-55-2

1-(tert-butoxycarbonyl)- azetidine-3-carboxylic acid 72925-16-7

(R)-1-(tert-butoxycar- bonyl)-pyrrolidine-3- carboxylic acid 84358-13-4

1-(tert-butoxycarbonyl)- piperidine-4-carboxylic acid 1126650-67-6

1-(tert-butoxycarbonyl)- 3-fluoroazetidine-3- carboxylic acid1158759-45-5

1-(tert-butoxycarbonyl)- 3-cyanoazetidine-3- carboxylic acid1035351-06-4

1-(tert-butoxycarbonyl)- 3-hydroxyazetidine-3- carboxylic acid429669-07-8

1-(tert-butoxycarbonyl)- 3-methoxyazetidine-3- carboxylic acid

TABLE CCi CAS# Structure Chemical Name 79-10-7

acrylic acid 98548-82-4

(E)-4-(dimethylamino)- but-2-enoic acid

Intermediate R9

tert-butyl 3-formyl-3-methoxyazetidine-1-carboxylate

Step 1: Preparation of 1-(tert-butyl) 3-methyl3-methoxyazetidine-1,3-dicarboxylate. A solution of 1-(tert-butyl)3-methyl 3-hydroxyazetidine-1,3-dicarboxylate (2.04 g, 8.82 mmol) in DMF(30 mL) was treated sequentially with NaH (60 wt. % dispersion inmineral oil, 0.529 g, 13.2 mmol) and Mel (0.659 mL, 10.6 mmol), thenstirred for 16 h at ambient temperature. Subsequently, the reactionmixture was diluted with water, and extracted with Et₂O (3×). Thecombined organic extracts were washed successively with water (3×) andbrine (1×), dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo. The resulting residue was purified by silica gelchromatography (using 5-75% Hexanes-EtOAc as the gradient eluent) toprovide the title compound (1.07 g, 50% yield).

Step 2: Preparation of tert-butyl3-(hydroxymethyl)-3-methoxyazetidine-1-carboxylate. A solution of1-(tert-butyl) 3-methyl 3-methoxyazetidine-1,3-dicarboxylate (Step 1;1.07 g, 4.362 mmol) in THF (44 mL) was treated LiBH₄ (0.3801 g, 17.45mmol), and stirred for 1 h at ambient temperature. The resulting mixturewas diluted with water, and extracted with DCM (3×). The combinedorganic extracts were dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo to cleanly afford the title compound (755.0 mg,80% yield).

Step 3: Preparation of tert-butyl3-formyl-3-methoxyazetidine-1-carboxylate. A cold (−78° C.) solution ofDMSO (987.3 μL, 13.90 mmol) in DCM (35 mL) was treated with oxalylchloride (882.1 μL, 10.43 mmol). After stirring for 15 min at −78° C.,the resulting mixture was treated with tert-butyl3-(hydroxymethyl)-3-methoxyazetidine-1-carboxylate (Step 2; 755.0 mg,3.475 mmol), stirred for an additional 15 min at −78° C., then treatedwith TEA (2906 μL, 20.85 mmol). Subsequently, the reaction mixture wasstirred for 1 h at ambient temperature. The mixture then was dilutedwith additional DCM, and washed with water (2×). The organic extractswere dried over anhydrous Na₂SO_(4(s)), filtered, and concentrated invacuo to provide cleanly the title compound (748.0 mg, quantitativeyield).

SYNTHETIC EXAMPLES Example 1

1-(3-(4-(4-(7-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carbonyl)azetidin-1-yl)prop-2-en-1-one

Step 1: Preparation of tert-butyl3-(4-(4-(7-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carbonyl)azetidine-1-carboxylate.A mixture ofN-(3,5-dimethoxyphenyl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinoxalin-6-amine(Intermediate P2; 198.9 mg, 0.4620 mmol),1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (102.27 mg, 0.50821mmol), HATU (193.2 mg, 0.5082 mmol) in DCM (4.6 mL) was treated withDIEA (1601 μL, 0.9240 mmol), then stirred overnight at ambienttemperature. Subsequently, the reaction mixture was concentrated invacuo, and the resulting residue was purified by silica gelchromatography (using 5-95% Hexanes-Acetone as the gradient eluent) tocleanly afford the title compound (quantitative yield assumed). MS(apci) m/z=614.3 (M+H).

Step 2: Preparation ofazetidin-3-yl(4-(4-(7-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methanone.A solution of tert-butyl3-(4-(4-(7-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carbonyl)azetidine-1-carboxylate(Step 1; 0.4620 mmol) in DCM (2.5 mL) was treated with TFA (2.5 mL),then stirred for 30 min at ambient temperature. Subsequently, thereaction mixture was concentrated in vacuo. The resulting oil was takenup in 4:1 DCM:iPrOH, and washed with saturated NaHCO_(3(aq)). Theorganic extracts then were dried over anhydrous Na₂SO_(4(s)), filtered,and concentrated in vacuo to afford the title compound (202 mg, 85%yield). MS (apci) m/z=514.2 (M+H).

Step 3: Preparation of1-(3-(4-(4-(7-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carbonyl)azetidin-1-yl)prop-2-en-1-one.A mixture ofazetidin-3-yl(4-(4-(7-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methanone(Step 2; 201.9 mg, 0.393106 mmol), acrylic acid (32.3 μL, 0.471 mmol),HATU (179.4 mg, 0.4717 mmol) in DCM (3.9 mL) was treated with DIEA(136.9 μL, 0.7862 mmol), then stirred overnight at ambient temperature.Subsequently, the reaction mixture was concentrated in vacuo, and theresulting residue was purified by C18 reverse phase chromatography(using 5-95% ACN-water with 0.1% TFA as the gradient eluent) to affordthe TFA salt of the title compound. The TFA salt was dissolved in 4:1DCM:iPrOH, and washed with saturated NaHCO_(3(aq)). The organic extractsthen were dried over anhydrous Na₂SO_(4(s)), filtered, and concentratedin vacuo to afford the title compound (132 mg, 59% yield). MS (apci)m/z=568.2 (M+H).

The compounds in Table C1 were prepared using a similar 3 Step method tothat described in the synthesis of1-(3-(4-(4-(7-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carbonyl)azetidin-1-yl)prop-2-en-1-one(Example 1), employing the following modifications: in Step 1, using1.1-3.0 equivalents of HATU, 2-5 equivalents of DIEA, solvent (DCM orDMF) concentration of 0.03-0.2 M and replacing both the1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid and theN-(3,5-dimethoxyphenyl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinoxalin-6-amine(Intermediate P2) respectively with 1.0-1.2 equivalents of theappropriate Boc-protected amino acid from Table CBi and 1.0 equivalentof the appropriate amine-core from the synthetic intermediates section(Table CA¹); and in Step 2, using DCM:TFA ratios between 1:1-2:1 byvolume and replacing the tert-butyl3-(4-(4-(7-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carbonyl)azetidine-1-carboxylate(Step 1) with the appropriate Boc-protected coupling product from Step1; and in Step 3, using 1.1-3.0 equivalents of HATU, 2-5 equivalents ofDIEA, solvent (DCM) concentration of 0.03-0.2 M and replacing both theacrylic acid andazetidin-3-yl(4-(4-(7-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methanone(Step 2) respectively with 1.0-1.2 equivalents of the appropriate acidfrom Table CCi and appropriate des-Boc product from Step 2 in each. Allreactions were monitored for completion by LCMS, as such reactiondurations were adjusted accordingly. When necessary, title compounds(Step 1 and/or Step 2 and/or Step 3) were purified via silica gelchromatographic purification using an appropriate gradient eluent orreverse phase chromatographic purification using an appropriate gradienteluent followed by a basic aqueous wash.

TABLE C1 MS (apci) Ex# Structure Chemical Name m/z  2

(R)-1-(3-(4-(4-(7-((3,5- dimethoxyphenyl)amino)- quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidine- 1-carbonyl)pyrrolidin-1- yl)-prop-2-en-1-one582.2 (M + H)  3

1-(4-(4-(4-(7-((3,5- dimethoxyphenyl)amino)- quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidine- 1-carbonyl)piperidin-1- yl)prop-2-en-1-one596.3 (M + H)  4

1-(3-(4-(4-(7-((3,5- dimethoxyphenyl)amino)- quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidine- 1-carbonyl)-3-fluoro- azetidin-1-yl)prop-2-en-1-one 586.2 (M + H)  5

1-(3-(4-(5-(7-((3,5- dimethoxyphenyl)amino)- quinoxalin-2-yl)pyridin-2-yl)piperazine-1- carbonyl)azetidin-1-yl)- prop-2-en-1-one 580.2 (M +H)  6

(E)-1-(3-(4-(5-(7-((3,5- dimethoxyphenyl)amino)-quinoxalin-2-yl)pyridin- 2-yl)piperazine-1- carbonyl)azetidin-1-yl)-4-(dimethylamino)but-2- en-1-one 637.3 (M + H)  7

(E)-1-(3-(4-(5-(7-((3,5- dimethoxyphenyl)amino)-quinoxalin-2-yl)pyridin-2- yl)piperazine-1-carbonyl)-3-fluoroazetidin-1-yl)-4- (dimethylamino)but-2-en- 1-one 655.3 (M + H) 8

1-(3-(4-(5-(7-((3,5- dimethoxyphenyl)amino)- quinoxalin-2-yl)pyridin-2-yl)piperazine-1-carbonyl)- 3-fluoroazetidin-1-yl)- prop-2-en-1-one 598.2(M + H)  9

(E)-1-(3-(4-(4-(7-((3,5- dimethoxyphenyl)amino)- quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidine-1- carbonyl)azetidin-1-yl)-4-(dimethylamino)but-2-en- 1-one 625.2 (M + H) 10

(E)-1-(3-(4-(4-(7-((3,5- dimethoxyphenyl)amino)- quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidine- 1-carbonyl)-3-fluoro- azetidin-1-yl)-4-(dimethylamino)but-2- en-1-one 643.3 (M + H) 11

(E)-3-(4-(4-(7-((3,5- dimethoxyphenyl)amino)- quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidine-1- carbonyl)-1-(4-(dimethyl- amino)but-2-enoyl)-azetidine-3-carbonitrile 650.3 (M + H) 12

1-acryloyl-3-(4-(4-(7- ((3,5-dimethoxyphenyl)- amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)- piperidine-1-carbonyl)- azetidine-3-carbonitrile 593.2(M + H) 13

(E)-1-(3-(4-(5-(7-((3,5- dimethoxyphenyl)amino)- quinoxalin-2-yl)-6-methylpyridin-2-yl)- piperazine-1-carbonyl)-3- fluoroazetidin-1-yl)-4-(dimethylamino)but-2- en-1-one 669.3 (M + H) 14

(E)-1-(3-(4-(5-(7-((3,5- dimethoxyphenyl)amino)- quinoxalin-2-yl)-4-methylpyridin-2-yl)- piperazine-1-carbonyl)- 3-fluoroazetidin-1-yl)-4-(dimethylamino)but-2-en- 1-one 669.3 (M + H) 15

1-(3-(4-(5-(7-((3,5- dimethoxyphenyl)amino)- quinoxalin-2-yl)-4-methylpyridin-2-yl)- piperazine-1-carbonyl)-3- fluoroazetidin-1-yl)prop-2-en-1-one 612.2 (M + H) 16

1-(3-(3-(4-(7-((3,5- dimethoxyphenyl)amino)- quinoxalin-2-yl)-1H-pyrazol-1-yl)azetidine-1- carbonyl)azetidin-1-yl)- prop-2-en-1-one 540.2(M + H) 17

(E)-1-(3-(4-(4-(7-((3,5- dimethoxyphenyl)amino)-quinoxalin-2-yl)-5-methyl- 1H-pyrazol-1-yl)piperi- dine-1-carbonyl)-3-fluoroazetidin-1-yl)-4- (dimethylamino)but-2- en-1-one 657.3 (M + H) 18

1-(3-(4-(4-(7-((3,5- dimethoxyphenyl)amino)- quinoxalin-2-yl)-5-methyl-1H-pyrazol-1-yl)piperi- dine-1-carbonyl)azetidin- 1-yl)prop-2-en-1-one582.3 (M + H) 19

(R,E)-1-(3-(3-(4-(7-((3,5- dimethoxyphenyl)amino)- quinoxalin-2-yl)-1H-pyrazol-1-yl)pyrrolidine- 1-carbonyl)-3-fluoro-azetidin-1-yl)-4-(dimethyl- amino)but-2-en-1-one 629.2 (M + H) 20

(R,E)-1-(3-(3-(4-(7-((3,5- dimethoxyphenyl)amino)- quinoxalin-2-yl)-1H-pyrazol-1-yl)pyrrolidine- 1-carbonyl)azetidin-1-yl)-4-(dimethylamino)but-2- en-1-one 611.3 (M + H) 21

(R)-1-(3-(3-(4-(7-((3,5- dimethoxyphenyl)amino)- quinoxalin-2-yl)-1H-pyrazol-1-yl)pyrrolidine- 1-carbonyl)azetidin-1- yl)prop-2-en-1-one554.2 (M + H) 22

(E)-1-(3-(4-(4-(7-((3,5- dimethoxyphenyl)amino)- quinoxalin-2-yl)-3-methyl-1H-pyrazol-1-yl)- piperidine-1-carbonyl)-3-fluoroazetidin-1-yl)-4- (dimethylamino)but-2-en- 1-one 657.3 (M + H) 23

(E)-1-(3-(4-(4-(7-((3,5- dimethoxyphenyl)amino)- quinoxalin-2-yl)-3,5-dimethyl-1H-pyrazol-1- yl)piperidine-1-carbonyl)-3-fluoroazetidin-1-yl)-4- (dimethylamino)but-2-en- 1-one 671.3 (M + H)24

1-(3-(4-(4-(7-((3,5- dimethoxyphenyl)amino)- quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidine- 1-carbonyl)-3-methoxy- azetidin-1-yl)prop-2-en-1-one 598.2 (M + H) 25

1-(3-(4-(3-(7-((3,5- dimethoxyphenyl)amino)- quinoxalin-2-yl)phenyl)-piperazine-1-carbonyl)- azetidin-1-yl)prop-2-en- 1-one 579.3 (M + H)

Example 26

1-(3-(4-(4-(7-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carbonyl)-3-hydroxyazetidin-1-yl)prop-2-en-1-one

The title compound (11.3 mg, 24% yield) was prepared in a similar 3 stepprocedure to that used in the preparation of1-(3-(4-(4-(7-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carbonyl)azetidin-1-yl)prop-2-en-1-one(Example 1).

¹H NMR (400 MHz, ef-DMSO) δ 8.96 (s, 1H), 8.80 (s, 1H), 8.65 (m, 1H),8.23 (s, 1H), 7.72 (m, 1H), 7.40 (m, 2H), 6.87 (s, 1H), 6.40 (m, 2H),6.32 (m, 1H), 6.16 (s, 1H), 6.09 (m, 1H), 5.64 (m, 1H), 4.70 (m, 1H),4.52 (m, 1H), 4.43 (m, 2H), 4.34 (m, 1H), 4.10 (m, 1H), 3.84 (m, 2H),3.72 (s, 6H), 2.73 (m, 1H), 2.08 (m, 2H), 1.98 (m, 1H), 1.84 (m, 1H).

Example 27

1-(3-(4-(4-(7-((3,5-dimethoxyphenyl)(methyl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carbonyl)-3-hydroxyazetidin-1-yl)prop-2-en-1-one

Step 1: Preparation of tert-butyl3-(4-(4-(7-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carbonyl)-3-hydroxyazetidine-1-carboxylate.A mixture ofN-(3,5-dimethoxyphenyl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinoxalin-6-amine(Intermediate P2; 100 mg, 0.232 mmol),l-[(tert-butoxy)carbonyl]-3-hydroxyazetidine-3-carboxylic acid (60.5 mg,0.279 mmol), HATU (265 mg, 0.697 mmol) in DCM (1.16 mL) was treated withDIEA (203 μL, 1.16 mmol), then stirred overnight at ambient temperature.Subsequently, the reaction mixture was concentrated in vacuo, and theresulting residue was purified by silica gel chromatography (using0-100% DCM-Acetone as the gradient eluent) to cleanly afford the titlecompound (135 mg, 92% yield).

Step 2: Preparation of tert-butyl3-((tert-butoxycarbonyl)oxy)-3-(4-(4-(7-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carbonyl)azetidine-1-carboxylate.A solution of tert-butyl3-(4-(4-(7-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carbonyl)-3-hydroxyazetidine-1-carboxylate(Step 147 mg, 0.075 mmol) in DCM (7464 μL) was treated withBoc-Anhydride (18 mg, 0.082 mmol), then stirred for 1 h at ambienttemperature. Subsequently, the reaction mixture was washed with brine(2×). The organic extracts then were dried over anhydrous Na₁SO_(4(s)),filtered and concentrated in vacuo to afford the title compound (54 mg,99% yield). MS (apci) m/z=730.3 (M+H).

Step 3: Preparation of tert-butyl3-((tert-butoxycarbonyl)oxy)-3-(4-(4-(7-((3,5-dimethoxyphenyl)(methyl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carbonyl)azetidine-1-carboxylate.A solution of tert-butyl3-((tert-butoxycarbonyl)oxy)-3-(4-(4-(7-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carbonyl)azetidine-1-carboxylate(Step 2; 54 mg, 0.074 mmol) in DMF (1480 μL) was treated sequentiallywith NaH (60 wt. % mineral oil dispersion; 2.66 mg, 0.111 mmol) and Mel(5.53 μL, 0.0888 mmol). The reaction mixture was stirred for 1 h atambient temperature, and then quenched with water and extracted withEtOAc. The organic extracts were washed with brine (2×), then dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo to afford thetitle compound (55 mg, 99% yield). MS (apci) m/z=744.3 (M+H).

Step 4: Preparation of(4-(4-(7-((3,5-dimethoxyphenyl)(methyl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(3-hydroxyazetidin-3-yl)methanone.A solution of tert-butyl3-((tert-butoxycarbonyl)oxy)-3-(4-(4-(7-((3,5-dimethoxyphenyl)(methyl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carbonyl)azetidine-1-carboxylate(Step 3; 55 mg, 0.074 mmol) in DCM (0.37 mL) was treated with TFA (0.37mL) and then stirred for 1 h at ambient temperature. The reactionmixture was concentrated in vacuo, quenched with saturated NaHCO_(3(aq))and extracted with 4:1 DCM:iPrOH. The organic layer was washed withbrine (2×), then dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to provide the title compound (40 mg, 100% yield).MS (apci) m/z=544.3 (M+H).

Step 5: Preparation of1-(3-(4-(4-(7-((3,5-dimethoxyphenyl)(methyl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carbonyl)-3-hydroxyazetidin-1-yl)prop-2-en-1-one.A mixture of(4-(4-(7-((3,5-dimethoxyphenyl)(methyl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(3-hydroxyazetidin-3-yl)methanone(Step 4; 40 mg, 0.0736 mmol), acrylic acid (6.06 μL, 0.0883 mmol) andHATU (83.9 mg, 0.221 mmol) in DCM (368 μL) was treated with DIEA (64.3μL, 0.368 mmol), then stirred overnight at ambient temperature.Subsequently, the reaction mixture was concentrated in vacuo, and theresulting residue was purified by C18 reverse phase chromatography(using 5-95% ACN-water with 0.1% TFA as gradient eluent) to afford theTFA salt of the title compound. The TFA salt was dissolved in 4:1DCM:iPrOH, and washed with saturated NaHCO_(3(aq)). The organic extractsthen were dried over anhydrous Na₂SO_(4(s)), filtered, and concentratedin vacuo to afford the title compound (8.9 mg, 20% yield). MS (apci)m/z=598.3 (M+H).

Example 28

(E)-1-(3-(4-(4-(7-((3,5-dimethoxyphenyl)(prop-2-yn-1-yl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carbonyl)-3-fluoroazetidin-1-yl)-4-(dimethylamino)but-2-en-1-one

Step 1: Preparation of tert-butyl3-(4-(4-(7-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carbonyl)-3-fluoroazetidine-1-carboxylate.A mixture ofN-(3,5-dimethoxyphenyl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinoxalin-6-amine(Intermediate P2; 400 mg, 0.929 mmol),1-(tert-butoxycarbonyl)-3-fluoroazetidine-3-carboxylic acid (204 mg,0.929 mmol), HATU (389 mg, 1.02 mmol) in DCM (16 mL) was treated withDIEA (0.324 mL, 1.86 mmol), then stirred for 3 d at ambient temperature.Subsequently, the reaction mixture was concentrated in vacuo, and theresulting residue was purified by silica gel chromatography (using50-100% EtOAc in Hexanes as the gradient eluent) to cleanly afford thetitle compound (502 mg, 85% yield). MS (apci) m/z=632.3 (M+H).

Step 2: Preparation of tert-butyl3-(4-(4-(7-((3,5-dimethoxyphenyl)(prop-2-yn-1-yl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carbonyl)-3-fluoroazetidine-1-carboxylate.A cold solution (0° C.) of tert-butyl3-(4-(4-(7-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carbonyl)-3-fluoroazetidine-1-carboxylate(Step 1; 230 mg, 0.3641 mmol) in DMF (7282 μL) was treated with NaH (60wt. % mineral oil dispersion; 21.84 mg, 0.5461 mmol), stirred for 5 min,then treated with 3-bromoprop-1-yne (60.83 μL, 0.5461 mmol). Thereaction mixture was stirred for 1 h at ambient temperature beforequenching with water and extracting with EtOAc. The organic extractswere washed with brine (2×), dried over anhydrous Na₂SO_(4(s)), filteredand concentrated in vacuo. The crude product was purified by silica gelchromatography (using 50-100% EtOAc in Hexanes as the gradient eluent)to afford the title compound (176 mg, 72% yield). MS (apci) m/z=670.3(M+H).

Step 3: Preparation of(4-(4-(7-((3,5-dimethoxyphenyl)(prop-2-yn-1-yl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(3-fluoroazetidin-3-yl)methanone.A solution of tert-butyl3-(4-(4-(7-((3,5-dimethoxyphenyl)(prop-2-yn-1-yl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carbonyl)-3-fluoroazetidine-1-carboxylate(Step 2; 0.176 g, 0.263 mmol) in DCM (2 mL) was treated with TFA (1 mL),then stirred for 10 min at ambient temperature. Subsequently, thereaction mixture was concentrated in vacuo, quenched with saturatedNaHCO_(3(aq)) and extracted with 4:1 DCM:iPrOH. The organic layer waswashed with brine (2×), dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to provide the title compound (150 mg, 100%yield). MS (apci) m/z=570.2 (M+H).

Step 4: Preparation of(E)-1-(3-(4-(4-(7-((3,5-dimethoxyphenyl)(prop-2-yn-1-yl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carbonyl)-3-fluoroazetidin-1-yl)-4-(dimethylamino)but-2-en-1-one.A solution of(4-(4-(7-((3,5-dimethoxyphenyl)(prop-2-yn-1-yl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(3-fluoroazetidin-3-yl)methanone(Step 3; 150 mg, 0.263 mmol), HATU (110 mg, 0.290 mmol), DIEA (460 μL,2.63 mmol) in DCM (5266 μL) was treated with(E)-4-(dimethylamino)but-2-enoic acid (37.4 mg, 0.290 mmol), and thenstirred for 16 h at ambient temperature. Subsequently, the reactionmixture was concentrated in vacuo. The resulting residue was purified byC18 reverse phase chromatography (using 5-95% ACN-water with 0.1% TFA asthe gradient eluent) to afford the TFA salt of the title compound. TheTFA salt was dissolved in 4:1 DCM:iPrOH, and washed with saturatedNaHCO_(3(aq)). The organic extracts then were dried over anhydrousNa₂SO_(4(s)), filtered, and concentrated in vacuo to afford the titlecompound (105 mg, 59% yield). MS (apci) m/z=681.3 (M+H).

Example 29

1-(3-((4-(4-(7-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-3-methoxyazetidin-1-yl)prop-2-en-1-one

Step 1: Preparation of tert-butyl3-((4-(4-(7-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-3-methoxyazetidine-1-carboxylate.A mixture ofN-(3,5-dimethoxyphenyl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinoxalin-6-amine(Intermediate P2; 50.0 mg, 0.116 mmol) and tert-butyl3-formyl-3-methoxyazetidine-1-carboxylate (Intermediate R9; 50.0 mg,0.232 mmol) in DCM (1161 μL) was treated with a few drops of AcOH (6.65μL, 0.116 mmol) and stirred for 30 min at ambient temperature. Theresulting mixture was treated with NaBH(OAc)₃ (29.5 mg, 0.139 mmol) andstirred for 3 h at ambient temperature. Subsequently, the reactionmixture was concentrated in vacuo, and the residue was purified bysilica gel chromatography (using 0-100% DCM:Acetone as the gradienteluent) to afford the title compound (50 mg, 68% yield). MS (apci)m/z=630.3 (M+H).

Step 2: Preparation ofN-(3,5-dimethoxyphenyl)-3-(1-(1-((3-methoxyazetidin-3-yl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)quinoxalin-6-amine.A solution of tert-butyl3-((4-(4-(7-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-3-methoxyazetidine-1-carboxylate(Step 1; 50 mg, 0.079 mmol) in DCM (0.4 mL) was treated with TFA (0.4mL), and then stirred for 1 h at ambient temperature. Subsequently, thereaction mixture was concentrated in vacuo, quenched with saturatedNaHCO_(3(aq)) and extracted with 4:1 DCM:iPrOH. The organic layer waswashed with brine (2×), dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to provide the title compound (42 mg, 100% yield).MS (apci) m/z=530.2 (M+H).

Step 3: Preparation of1-(3-((4-(4-(7-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-3-methoxyazetidin-1-yl)prop-2-en-1-one.A mixture ofN-(3,5-dimethoxyphenyl)-3-(1-(1-((3-methoxyazetidin-3-yl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)quinoxalin-6-amine(Step 2; 42 mg, 0.0793 mmol), acrylic acid (5.99 μL, 0.0872 mmol) andHATU (90.5 mg, 0.238 mmol) in DCM (396 μL, 0.0793 mmol) was treated withDIEA (69.3 μL, 0.396 mmol), then stirred for 2 h at ambient temperature.Subsequently, the reaction mixture was concentrated in vacuo, and theresulting residue was purified by silica gel chromatography (using0-100% DCM:Acetone as the gradient eluent) to afford the title compound(35 mg, 75% yield). MS (apci) m/z=584.3 (M+H).

Example 30

1-(3-((4-(4-(7-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)azetidin-1-yl)prop-2-en-1-one

The title compound (34.5 mg, 75% yield) was prepared using a similar 3step method to that described in the synthesis of1-(3-((4-(4-(7-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-3-methoxyazetidin-1-yl)prop-2-en-1-one(Example 32), except in Step 1 tert-butyl3-formyl-3-methoxyazetidine-1-carboxylate was replaced with tert-butyl3-formylazetidine-1-carboxylate. MS (apci) m/z=554.3 (M+H).

Abbreviations:

Abbreviation IUPAC name ACN Acetonitrile AcOH Acetic AcidBis(pinacolato)diboron4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) Boctert-butyl carboxylate group Boc-anhydride di-tert-butyl dicarbonate dday, days DCM Dichloromethane DIEA N,N-Diisopropylethylamine dioxane1,4-dioxane DMA N,N-Dimethylacetamide DME 1,2-Dimethoxyethane DMFN,N-Dimethylformamide DMSO Dimethylsulfoxide Et₂O Diethyl Ether EtOAcEthyl Acetate h hour, hours HATU1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate or 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HBTU3-[Bis(dimethylamino)methyliumyl]-3H-benzotriazol-1-oxidehexafluorophosphate or 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate iPrOH Isopropanol KOAc PotassiumAcetate LCMS Liquid chromatography-mass spectrometry Mel iodomethaneMeOH Methanol min minute, minutes NaBH(OAc)₃ SodiumTriacetoxyborohydride NaOtBu Sodium tert-Butoxide n-BuLi n-butyl lithiumor 1-butyl lithium Pd(PPh₃)₄ Tetrakis(triphenylphosphine)palladium (0)PdCl₂(dppf)•CH₂Cl₂1,1-Bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex TEA Triethylamine TFA Trifluoroacetic acid THFtetrahydrofuran

Biological Activity

Example A FGFR Enzyme Binding Assay

The potency of compounds inhibiting human isoforms of FGFR kinase wasdetermined using Life Technologies' Homogeneous Time ResolvedFluorescence (HTRF)-based binding assay technology. An incubation wasconducted with either 5 nM dephosphorylated FGFR1 (Array Biopharma,p1702; SEQ ID NO: 1, amino acids 458 to 765, dephosphorylated byco-expression with PTP1b (protein tyrosine phosphatase 1B)), 5 nMdephosphorylated FGFR2 (Life Technologies, Cat. No. PV4106 that had beendephosphorylated with Lambda protein phosphatase (New England Biolabs,cat #P0753)) or 5 nM phosphorylated FGFR3 (Array Biopharma, p1836; SEQID NO: 5, amino acids 449 to 759), 50 nM Kinase Tracer 236 (LifeTechnologies Cat. No. PR9078A), 2 nM Biotin-anti-6HIS (Life TechnologiesCat. No. PV6090) and 2 nM Europium-Streptavidin (Life Technologies Cat.No. PV6025) along with test compound in a buffer consisting of 50 mMHEPES ((4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, pH 7.5), 5mM MgCl₂, 0.005% Triton X-100, 1 mM DTT, 1 mM NaVO₄ and 2% DMSO in afinal volume of 12 μL Compounds were typically prepared as a 3-fold or4-fold serial dilution in DMSO and added to the assay to give theappropriate final concentration. After a 60 minute incubation at 22° C.,the extent of tracer displacement was determined using a PerkinElmerEnVision multimode plate reader via HTRF dual wavelength detection, andthe percent of control (POC) was calculated using a ratiometric emissionfactor. One hundred POC was determined using no test compound, and 0 POCwas determined in the presence of 1 μM of an appropriate controlinhibitor. A 4-parameter logistic curve was fit to the POC values as afunction of the concentration of compound, and the IC₅₀ value was thepoint where the best-fit curve crossed 50 POC.

Table EA contains IC₅₀ values for compounds tested in this assay,presented as the average of multiple determinations if multipledeterminations were made. ND=not determined.

TABLE EA FGFR Enzyme Binding IC₅₀ values FGFR1 Enz FGFR2 Enz FGFR3 EnzExample Binding IC₅₀ Binding IC₅₀ Binding IC₅₀ Number (nM) (nM) (nM) 122 3 2 2 24 6 4 3 26 5 5 4 33 4 3 5 623 ND 59 6 132 14 9 7 342 18 11 8558 ND 30 9 22 ND 2 10 28 6 3 11 44 ND 3 12 48 ND 3 13 6624 ND 335 144142 290 123 15 2367 ND 116 16 30 ND 5 17 102 ND 5 18 244 ND 18 19 55 ND4 20 53 ND 5 21 38 ND 5 22 131 19 4 23 842 38 13 24 53 8 9 25 759 157327 26 37 5 6 27 13 3 6 28 6 3 2 29 50 5 3 30 34 5 3

Example B FGFR Enzyme Activity Assay

FGFR1 kinase activity was measured by the Invitrogen LanthaScreen™ Assaytechnology which directly measures the amount of substratephosphorylation by Time-resolved fluorescence energy transfer (TR-FRET)using a flourescently-labeled peptide and Europium-labeled antibody.Briefly, 200 pM His-tagged recombinant human FGFR1 catalytic domain(amino acids 308-731) (Life Technologies Cat. No. PR4660A) was incubatedwith 100 nM Alexa Fluor® 647-Poly-GT Peptide Substrate (LifeTechnologies Cat. No. PV5836) and 15 μM ATP along with test compound ina buffer consisting of 250 mM HEPES, 25 mM MgCl2, 0.05% TritonX-100, pH7.5, and 2% DMSO. Compounds were typically prepared in a threefoldserial dilution in DMSO and added to the assay to give the appropriatefinal concentration. After a 20 minutes incubation at 22° C., an equalvolume of 2 nM LanthaScreen® Eu-PY20 Antibody (Life Technologies Cat.No. PV5691) and 10 mM EDTA was added to quench the kinase reaction andstart the detection reaction. After an additional 60 minute incubationat 22° C., the reaction was measured using a PerkinElmer EnVisionmultimode plate reader via TR-FRET dual wavelength detection, and thepercent of control (POC) calculated using a ratiometric emission factor.100 POC was determined using no test compounds and 0 POC was determinedusing no enzyme. The POC values were fit to a 4-parameter logistic curveas a function of the concentration of the compound, and the IC₅₀ valueis the point where the curve crosses 50 POC.

FGFR2 kinase activity was measured by the Invitrogen LanthaScreen™ Assaytechnology which directly measures the amount of substratephosphorylation by TR-FRET using a flourescently-labeled peptide andEuropium-labeled antibody. Briefly, 200 pM His-tagged recombinant humanFGFR2 cytoplasmic domain (amino acids 403-822) (Life Technologies Cat.No. PR5332A) was incubated with 100 nM Alexa Fluor® 647-Poly-GT PeptideSubstrate (Life Technologies Cat. No. PV5836) and 15 μM ATP along withtest compound in a buffer consisting of 250 mM HEPES, 25 mM MgCl2, 0.05%TritonX-100, pH 7.5, and 2% DMSO. Compounds were typically prepared in athreefold serial dilution in DMSO and added to the assay to give theappropriate final concentration. After a 20 minute incubation at 22° C.,an equal volume of 2 nM LanthaScreen® Eu-PY20 Antibody (LifeTechnologies Cat. No. PV5691) and 10 mM EDTA were added to quench thekinase reaction and start the detection reaction. After an additional 60minute incubation at 22° C., the reaction was measured using aPerkinElmer EnVision multimode plate reader via TR-FRET dual wavelengthdetection, and the percent of control (POC) calculated using aratiometric emission factor. 100 POC was determined using no testcompounds and 0 POC was determined using no enzyme. The POC values werefit to a 4-parameter logistic curve as a function of the concentrationof the compound, and the IC₅₀ value is the point where the curve crosses50 POC.

FGFR3 kinase activity was measured by the Invitrogen LanthaScreen™ Assaytechnology which directly measures the amount of substratephosphorylation by TR-FRET using a flourescently-labeled peptide andEuropium-labeled antibody. Briefly, 750 pM N-terminal GST-HIS6 fusionprotein with a 3C cleavage site recombinant human FGFR3 (amino acidsR397-T806) (ProQinase Cat. No. 1068-0000-1) was incubated with 100 nMAlexa Fluor® 647-Poly-GT Peptide Substrate (Life Technologies Cat. No.PV5836) and 25 μM ATP along with test compound in a buffer consisting of250 mM HEPES, 25 mM MgCl2, 0.05% TritonX-100, pH 7.5, and 2% DMSO.Compounds were typically prepared in a threefold serial dilution in DMSOand added to the assay to give the appropriate final concentration.After a 10 minute incubation at 22° C., an equal volume of 2 nMLanthaScreen® Eu-PY20 Antibody (Life Technologies Cat. No. PV5691) and10 mM EDTA were added to quench the kinase reaction and start thedetection reaction. After an additional 60 minute incubation at 22° C.,the reaction was measured using a PerkinElmer EnVision multimode platereader via TR-FRET dual wavelength detection, and the percent of control(POC) calculated using a ratiometric emission factor. 100 POC wasdetermined using no test compounds and 0 POC was determined using noenzyme. The POC values were fit to a 4-parameter logistic curve as afunction of the concentration of the compound, and the IC₅₀ value is thepoint where the curve crosses 50 POC.

Table EB contains IC₅₀ values for compounds tested in these assays,presented as the average of multiple determinations if multipledeterminations were made. ND=Not determined.

TABLE EB FGFR Enzyme Activity IC₅₀ values FGFR1 Enz FGFR2 Enz FGFR3 EnzExample FRET IC₅₀ FRET IC₅₀ FRET IC₅₀ Number (nM) (nM) (nM) 1 54 11 9 249 11 10 3 51 12 10 4 89 40 10 5 448 365 272 6 216 124 161 7 364 227 2778 831 744 631 9 29 10 23 10 35 11 16 11 44 15 7 12 89 33 13 13 2146 19141834 14 1555 666 490 15 5000 5000 5000 16 48 27 18 17 376 118 48 18 1212555 373 19 288 166 50 20 194 107 42 21 295 187 37 22 339 84 79 23 50003460 972 24 229 211 24 25 1765 1742 479 26 118 121 14 27 10 12 2 28 21 56 29 414 333 40 30 147 159 26

Example C FGFR k_(obs) Assay

The LC/MS FGFR1 and FGFR3 k_(obs) assays were conducted as follows. 500nM FGFR1 (Array BioPharma construct p1702; SEQ ID NO: 1, amino acids458-765) or FGFR3 (Array BioPharma construct p1700; SEQ ID NO: 5, aminoacids 449-759) were incubated with 3 μM compound in 25 mM HEPES(4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), pH 7.4, 5 mMMgCl2, 150 mM NaCl, 0.5 mM TCEP (tris(2-carboxyethyl) phosphine), and 2%DMSO in a total volume of 20 μL. At each time point, the reaction wasquenched with 20 μL of 0.4% formic acid. The extent of proteinmodification by each compound was determined by LC/MS on an AgilentTechnologies 6520 Q-TOF LC/MS. Protein signals were then automaticallydeconvoluted using Agilent Masshunter software. Deconvoluted masssignals were exported to Tibco Spotfire data analysis program forfurther processing and normalization.

Data analysis included five steps. First, the signals for the “DMSOControls” were analyzed to determine the percent of signal associatedwith unmodified FGFR1 or FGFR3 at each time point. Next, the percent ofthe signal associated with the covalent modification was determined.Third, the average nonmodified “DMSO Control” signal was used tonormalize the modified protein signals at each time point. The percentof unmodified protein was fit to an exponential decay model where A₀ isthe Percent Unmodified at the start of the reaction, and k_(obs) is theobserved rate constant over the time period.

Table EC contains k_(obs) values for compounds tested in these assays,presented as the average of multiple determinations if multipledeterminations were made. ND=not determined.

TABLE EC k_(obs) values Example FGFR1 Enz k_(obs) FGFR3 Enz k_(obs)Number (min⁻¹) (min⁻¹) 1 0.00127 0.00945 2 0.00038 0.00302 3 ND 0.001664 0.00632 0.03901 5 0.00110 0.01486 6 0.00259 0.04816 7 0.00659 0.130898 0.00384 0.06319 9 0.00278 0.02139 10 0.01569 0.09291 11 0.018220.14732 12 0.01070 0.07246 13 0.00293 0.02606 14 0.00326 0.04226 150.00154 0.01720 16 0.00151 0.01232 17 0.00842 0.08024 18 0.00096 0.0146219 0.00339 0.03902 20 0.00141 0.00892 21 0.00106 0.00664 22 0.006730.05725 23 0.00386 0.07588 24 0.00223 0.01322 25 0.00404 0.00369 260.00288 0.01414 27 0.00264 0.00987 28 0.01569 0.07800 29 0.00250 0.0167130 0.00172 0.01591

Example D FGFR pERK Assay

FGFR1 pERK Cell Assay:

HEK-293 cells transfected with doxycycline(dox)-inducible human wildtype FGFR1 (SEQ ID NO: 1) were plated in a collagen or poly-D-lysinecoated 96 well flat bottom plates at 4×10⁵ cells/well in completeDulbecco's Modified Eagle Medium (DMEM) containing 10% FBS and 1 μg/mldoxycycline and allowed to attach for 24 h at 37° C., 5% CO₂. Cells weretreated with compound using 1:3 serial dilutions with a maximum finalconcentration of 5 μM. Compound was incubated on cells for 1 hour at 37°C., 5% CO₂. Cells were then stimulated with a final concentration of 100ng/ml human FGF-acidic (R&D Systems Cat number 232-FA/CF) for 5 minutesat 37° C., 5% CO2. Medium was removed, and cells were lysed with lysisbuffer containing phosphatase and protease inhibitors. Phospho ERK1/2was measured using the Meso Scale Discovery sandwich assay (Meso ScaleDiscovery cat. no. K151DWD). The assay captures phospho ERK1/2 anddetects with a sulfo-tagged total ERK1/2 antibody. The chemiluminescentsignal was read on the Sector Imager Plate reader. 100 POC wasdetermined using no test compound and 0 POC was determined using acontrol compound. The POC values were fit to a 4-parameter logisticcurve as a function of the concentration of the compound, and the IC₅₀value is the point where the curve crosses 50 POC.

FGFR2 pERK Cell Assay:

HEK-293 cells transfected with dox-inducible human wild type FGFR2 (SEQID NO: 3) are plated in a collagen or poly-D-lysine coated 96 well flatbottom plates at 4×10⁵ cells/well in complete DMEM medium containing 10%FBS and 1 μg/ml doxycycline and allowed to attach for 24 h at 37° C., 5%CO₂. Cells are treated with compound using 1:3 serial dilutions with amaximum final concentration of 5 μM. Compound is incubated on cells for1 hour at 37° C., 5% CO₂. Cells are then stimulated with a finalconcentration of 30 ng/ml human FGF-acidic (R&D Systems Cat number232-FA/CF) for 5 minutes at 37° C., 5% CO₂. Medium is removed, and cellsare lysed with lysis buffer containing phosphatase and proteaseinhibitors. Phospho ERK1/2 is measured using the Meso Scale Discoverysandwich assay (Meso Scale Discovery cat. no. K151DWD). The assaycaptures phospho ERK1/2 and detects with a sulfo-tagged total ERK1/2antibody. The chemiluminescent signal is read on the Sector Imager Platereader. 100 POC is determined using no test compounds and 0 POC isdetermined using a control compound. The POC values are fit to a4-parameter logistic curve as a function of the concentration of thecompound, and the IC₅₀ value is the point where the curve crosses 50POC.

FGFR3 pERK Cell Assay:

HEK-293 cells transfected with dox-inducible human wild type FGFR3 (SEQID NO: 5) were plated in a collagen or poly-D-lysine coated 96 well flatbottom plates at 4×10⁵ cells/well in complete DMEM medium containing 10%FBS and 1 μg/ml doxycycline and allowed to attach for 24 h at 37° C., 5%CO₂. Cells were treated with compound using 1:3 serial dilutions with amaximum final concentration of 5 μM. Compound was incubated on cells for1 hour at 37° C., 5% CO₂. Cells were then stimulated with a finalconcentration of 100 ng/ml human FGF-acidic (R&D Systems Cat number232-FA/CF) for 5 minutes at 37° C., 5% CO₂. Medium was removed, andcells were lysed with lysis buffer containing phosphatase and proteaseinhibitors. Phospho ERK1/2 was measured using the Meso Scale Discoverysandwich assay (Meso Scale Discovery cat. no. K151DWD). The assaycaptures phospho ERK1/2 and detects with a sulfo-tagged total ERK1/2antibody. The chemiluminescent signal was read on the Sector ImagerPlate reader. 100 POC was determined using no test compounds and 0 POCwas determined using a control compound. The POC values were fit to a4-parameter logistic curve as a function of the concentration of thecompound, and the IC₅₀ value is the point where the curve crosses 50POC.

Table ED contains IC₅₀ values for compounds tested in these assays,presented as the average of multiple determinations if multipledeterminations were made. ND=not determined.

TABLE ED pERK cell IC₅₀ values FGFR1 Cell FGFR3 Cell Example pERK IC₅₀pERK IC₅₀ Number (nM) (nM) 1 507 44 2 852 207 3 350 135 4 170 20 5 2693317 6 5000 228 7 1531 77 8 1144 154 9 2230 184 10 134 14 11 149 19 12149 22 13 ND ND 14 1942 540 15 5000 528 16 3003 397 17 423 61 18 3659216 19 1276 114 20 5000 2744 21 1894 390 22 898 113 23 1939 699 24 22519 25 ND ND 26 1650 153 27 128 12 28 34 8 29 206 25 30 225 24

Example E pFGFR Assay

FGFR1 pFGFR Cell Assay:

HEK-293 cells transfected with dox-inducible human wild type FGFR1 (SEQID NO: 1) are plated in a collagen or poly-D-lysine coated 96 well flatbottom plates at 4×10⁵ cells/well in complete DMEM medium containing 10%FBS and 1 μg/ml doxycycline and allowed to attach for 24 h at 37° C., 5%CO₂. Cells are treated with compound using 1:3 serial dilutions with amaximum final concentration of 5 μM. Compound is incubated on cells for1 hour at 37° C., 5% CO₂. Medium is removed, and cells are lysed withlysis buffer containing phosphatase and protease inhibitors. PhosphoFGFR1 is measured by ELISA (R&D Systems cat. no. DYC5079 or CellSignaling Technology cat. no. 12909). The ELISA captures total FGFR1 anddetects total phospho tyrosine. Optical density is measured for eachwell using a Versamax reader at a wavelength of 450 nm. 100 POC isdetermined using no test compounds and 0 POC is determined using acontrol compound. The POC values are fit to a 4-parameter logistic curveas a function of the concentration of the compound, and the IC₅₀ valueis the point where the curve crosses 50 POC.

FGFR2 pFGFR Cell Assay:

HEK-293 cells transfected with dox-inducible human wild type FGFR2 (SEQID NO: 3) were plated in a collagen or poly-D-lysine coated 96 well flatbottom plates at 4×10⁵ cells/well in complete DMEM medium containing 10%FBS and 1 μg/ml doxycycline and allowed to attach for 24 h at 37° C., 5%CO₂. Cells were treated with compound using 1:3 serial dilutions with amaximum final concentration of 5 μM. Compound was incubated on cells for1 hour at 37° C., 5% CO₂. Cells were then stimulated with a finalconcentration of 30 ng/ml human FGF-acidic (R&D Systems Cat number232-FA/CF) for 5 minutes at 37° C., 5% CO₂. Medium was removed and cellswere lysed with lysis buffer containing phosphatase and proteaseinhibitors. Phospho FGFR2 was measured by ELISA (R&D Systems cat. no.DYC684). The ELISA captures total FGFR2 and detects total phosphotyrosine. Optical density was measured for each well using a Versamaxreader at a wavelength of 450 nm. 100 POC was determined using no testcompounds and 0 POC was determined using a control compound. The POCvalues were fit to a 4-parameter logistic curve as a function of theconcentration of the compound, and the IC₅₀ value is the point where thecurve crosses 50 POC.

FGFR3 pFGFR Cell Assay:

HEK-293 cells transfected with dox-inducible human wild type FGFR3 (SEQID NO: 5) were plated in a collagen or poly-D-lysine coated 96 well flatbottom plates at 4×10⁵ cells/well in complete DMEM medium containing 10%FBS and 1 μg/ml doxycycline and allowed to attach for 24 h at 37° C., 5%CO₂. Cells were treated with compound using 1:3 serial dilutions with atop final concentration of 5 μM. Compound was incubated on cells for 1hour at 37° C., 5% CO₂. Cells were then stimulated with a finalconcentration of 100 ng/ml human FGF-acidic for 5 minutes at 37° C., 5%CO₂. Medium was removed and cells were lysed with lysis buffercontaining phosphatase and protease inhibitors. Phospho FGFR3 wasmeasured by ELISA (R&D Systems cat DYC2719). The ELISA captures totalFGFR3 and detects total phospho tyrosine. Optical density was measuredfor each well using a Versamax reader at a wavelength of 450 nm. 100 POCwas determined using no test compounds and 0 POC was determined using acontrol compound. The POC values were fit to a 4-parameter logisticcurve as a function of the concentration of the compound, and the IC₅₀value is the point where the curve crosses 50 POC.

Table EE contains IC₅₀ values for compounds tested in these assays,presented as the average of multiple determinations if multipledeterminations were made. ND=not determined.

TABLE EE pFGFR cell IC₅₀ values FGFR2 Cell FGFR3 Cell Example pFGFR IC₅₀pFGFR IC₅₀ Number (nM) (nM) 1 140 35 2 117 121 3 69 89 4 ND 17 5 486 ND7 182 ND 10 28 ND 17 170 ND 22 301 ND 24 49 ND 27 37 ND 28 6 ND 29 56 ND30 62 ND

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

INCORPORATION BY REFERENCE

The entire contents of all patents, published patent applications,websites, and other references cited herein are hereby expresslyincorporated herein in their entireties by reference.

1. A compound of Formula I

and pharmaceutically acceptable salts and solvates thereof, wherein: R¹is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl; Ring A is Ar¹or hetAr¹; Ar¹ is phenyl optionally substituted with 1-2 independentlyselected halogen or C1-C6 alkyl; hetAr¹ is a 5-6 membered heteroarylring having 1-3 ring nitrogen atoms and optionally substituted with 1-2independently selected halogen or C1-C6 alkyl; Ring B is a 4-6 memberedsaturated heterocyclic ring wherein X¹ is CH or N and X² is N; L isC(═O)— or —CH₂—; Ring C is a 4-6 membered saturated heterocyclic ringwherein X³ is N, wherein said ring is optionally substituted withhalogen, CN, OH, C1-C6 alkoxy, or C1-C6 alkyl; W is R²R³C═CR⁴C(═O)—,R⁵R⁶NCH₂CH═CHC(═O)—, H₂C═CHSO₂— or R⁷C≡CC(═O)—; R² is hydrogen; R³ ishydrogen, CF₃ or Z(C1-C6 alkyl)- wherein Z is H, F, C1, Br, HO—, C1-C6alkoxy, or fluoro C1-C6 alkoxy, and R⁴ is hydrogen, C1-C3 alkyl, fluoroC1-C3 alkyl or halogen, or R³ and R⁴ together with the carbon atoms towhich they are attached form a 4-8-membered carbocylic ring; R⁵ and R⁶are each independently selected C1-C6 alkyl, or R⁵ and R⁶ together withthe nitrogen atom to which they are attached form a 5-6 memberedheterocyclic ring optionally having an additional ting heteroatom whichis O, wherein said ting is optionally substituted with halogen; R⁷ ishydrogen, C1-C3 alkyl, HO-C1-C3 alkyl or R′R″NCH₂—; and R¹ and R^(N) areeach independently hydrogen or C1-C6 alkyl.
 2. A compound according toclaim 1, wherein R¹ is selected from —H, —CH₃, and, —CH₂CN
 3. A compoundaccording to claim 1, wherein Ring A is hetAr¹ and is selected from thefollowing:

wherein the asterisk represents point of attachment to Ring B, andpharmaceutically acceptable salts thereof.
 4. A compound according toclaim 1, wherein Ring A is Ar¹ and is

wherein the asterisk represents point of attachment to Ring B, andpharmaceutically acceptable salts thereof.
 5. A compound according toclaim 1, wherein Ring B is selected from the following:

wherein the asterisk represents point of attachment to L, andpharmaceutically acceptable salts thereof.
 6. A compound according toclaim 1, wherein L is selected from —C(═O)— and, —CH₂—, andpharmaceutically acceptable salts thereof.
 7. A compound according toclaim 1, wherein Ring C is selected from the following:

wherein the asterisk indicates the point of attachment to W, andpharmaceutically acceptable salts thereof.
 8. A compound according toclaim 1, wherein W is selected from (CH₃)NCH₂CH═CHC(═O)— and,CH₂═CHC(═O)—, and pharmaceutically acceptable salts thereof.
 9. A methodfor treating cancer in a subject in need thereof, the method comprisingadministering to the subject a pharmaceutical composition comprising atherapeutically effective amount of a compound according to claim 1, ora pharmaceutically acceptable salt thereof.
 10. The method of claim 9,wherein the cancer is an FGFR-associated cancer.
 11. The method of claim10, wherein the FGFR-associated cancer is selected from the groupconsisting of: bladder cancer, brain cancer, breast cancer,cholangiocarcinoma, head and neck cancer, lung cancer, multiple myeloma,rhabdomyosarcoma, urethral cancer, and uterine cancer.
 12. The method ofclaim 10, wherein the FGFR-associated cancer is a FGFR fusion lungcancer, a FGFR fusion breast cancer, a FGFR fusion bladder cancer, aFGFR fusion biliary tract cancer, a FGFR fusion urethral cancer, a FGFRfusion head and neck cancer, or a FGFR fusion multiple myeloma.
 13. Themethod of claim 10, wherein the FGFR-associated cancer is lung cancer,and the lung cancer is small cell lung carcinoma, non-small cell lungcancer, squamous cell lung cancer, or lung adenocarcinoma.
 14. Themethod of claim 9, wherein the compound or a pharmaceutically acceptablesalt thereof is orally administered. 15-21. (canceled)
 22. Apharmaceutical composition, comprising a compound or a pharmaceuticallyacceptable salt thereof according to claim 1 with one or morepharmaceutically acceptable carriers, diluents, or excipients.